StemCell Therapy

Continuing Education Activity

Molecular diagnostics encompasses the analysis of human, viral, and microbial genomesand the products they encode. Molecular genetics utilizesmolecular biology's laboratory tools to relate genetic structureto protein function and, ultimately, health and disease.Variants identified during genetic testing are classified based on diverse evidence types, as the American College of Medical Genetics and Genomics recommends, emphasizing the need for board-certified geneticists to interpret the results.Integrating genetic testing methodologies with clinical expertise is crucial in translating molecular genetics advancements tobetter patient care.

The field of molecular genetic and genomic testing is undergoing rapid change due to improvements in our understanding of the molecular causes of uncommon and common illnesses and DNA analysis technologies.The advent of molecular genetics has revolutionized healthcare by offering unprecedented insights into the genetic basis of diseases, enabling personalized diagnostics, treatment strategies, and risk assessments. However, this progress brings with it the responsibility for healthcare providers to stay updated with the latest advancements and best practices in genetic testing.

This activity for healthcare professionals is designed to enhance learners' proficiency in identifying patients withindications for molecular genetics testing and interpreting genetic test results. Participants acquire a broader grasp of specimen collection, procedures, indications, potential diagnosis, normal and critical findings, interfering factors, and complications. Learners gain insights into thecomplexities of molecular genetics, preparing them to collaborate with an interprofessional team that aims to improve outcomes for patients who need molecular genetics testing.

Objectives:

Identify clinicalencounters appropriate for genetic molecular testing, distinguishing cases where such testing can contribute to diagnosis, prognosis, or treatment decisions.

Evaluate genetic test results accurately, discerning their clinical significance and relevance to patient management.

Differentiatebetween genetic testing methodologies, understanding their strengths, limitations, and optimal applications to diagnose patients.

Implement best interprofessional collaboration and communication practices to ensure that patientswho need molecular genetics testing receive comprehensive care that considers their medical, psychological, and social needs, thus improving outcomes.

Molecular genetics testing is fundamental in evaluating inherited disorders, somatic or acquired diseases with genetic associations, and pharmacogenetic responses. Genotyping can provide valuable disease diagnosis, prognosis, and progression indicators, guide treatment selection and response, and identify gene-specific therapeutic targets.[1]Human genetic material primarily consists of double-stranded, helical DNA. This molecule has a backbone composed of alternating sugar (deoxyribose) and phosphate groups, with hydrogen bonds linking nitrogenous base pairs. Specifically, adenine (purine) pairs with thymine (pyrimidine), while guanine (purine) pairs with cytosine (pyrimidine), forming the complementary base pairs within the DNA double helix.[2][3]

DNA in human cells is wrapped around histone proteins and packaged into nucleosome units, compacted further to form chromosomes.[4]Somatic cells normally have 23 chromosome pairs, with 1 pair comprised of the sex chromosomes X and Y. Each chromosome has DNA with a terminal stretch of short repeats called telomeres and additional repeats in the centromere region.[5]

Humans have 2 sets of 23 chromosomes, one derived from the mothers egg and the other from the father's sperm. Therefore, each egg and sperm is a single or haploid set of 23 chromosomes. Combining the 2 creates a diploid set of human DNA, allowing each individual to possess 2 different sequences, genes, and alleles on each chromosome.[6]Homologous recombination during meiosis generates unique allele combinations in gametes, leading to genetic diversity among offspring in the human population.[7]

The complete decoding of the human genome sequence and the development of powerful identification and cloning methods for genes linked to inherited diseases have transformed the practice of molecular genetics and molecular pathology. Advanced molecular analysis methods can now determine presymptomatic individuals' illness risk, detect asymptomatic recessive trait carriers, and prenatally diagnose conditions not yet evident in pregnancy.[8]Molecular genetics techniques are often the only approaches to these puzzles. Thus, genetic tests are powerful tools for diagnosis, genetic consultation, and prevention of heritable diseases.[9]

Many genetic testscan analyze gene, chromosome, and protein alterations. A clinician often considers several factors when selecting the appropriate test, including suspected conditions and their possible genetic variations. A broad genetic test is employed when a diagnosis is uncertain, while a targeted test is preferred for suspected specific conditions.[10]Molecular tests look for changes in 1 or more genes. These tests analyze the sequence of DNA building blocks (nucleotides) in an individual's genetic code, a process known as DNA sequencing, which can vary in scope.[11]

The targeted single variant test identifies a specific variant in a single gene known to cause a disorder, eg, the HBB gene variant causing-globin abnormalities that give rise to sickle cell disease. This test assesses the family members of an individual with the known variant to ascertain if they have the familial condition.[12]Single-gene tests examine genetic alterations in 1 gene to confirm or rule out a specific diagnosis, notably when many variants in the gene can cause the suspected condition. Gene panel tests look for variants in multiple genes to pinpoint a diagnosis when a person has symptoms that may fit various conditions or when many gene variants can cause the suspected condition.[13][14]

Whole-exome sequencing or whole-genome sequencing tests analyze the bulk of an individual's DNA to find genetic variations. This approach is useful when a single-gene or panel testing has not provided a diagnosis or when the suspected condition or genetic cause is unclear.[15]This sequencing method is often more cost- and time-effective than performing multiple single gene or panel tests.[16]

Chromosomal tests analyze whole chromosomes or long DNA lengths to identify significant alterations, including extra or missing chromosome copies (trisomy or monosomy), large chromosomal segment duplications or deletions, and segment rearrangements (translocations) (see Image. Trisomy 21on G-Banded Chromosomal Studies).[17]Chromosomal tests are employed when specific genetic conditions linked to chromosomal changes are suspected. For instance, Williams syndrome results from deleting a chromosome 7 segment.

Gene expression tests assess gene activation status in cells, indicating whether genes are active or inactive, with activated genes producing mRNA molecules that serve as templates for protein synthesis.[18]The mRNA produced helps determine which genes are highly active. Too much activity (overexpression) or too little activity (underexpression) of specific genes may suggest particular genetic disorders, including various cancer types.[19]Biochemical tests assess protein or enzyme levels and activity rather than directly analyzing DNA.[20]Abnormalities in these substances may indicate DNA changes underlying a genetic disorder.

Heritable mutations are detectable in all nucleated cells and are thus considered germline or constitutional genetic changes. Somatic genetic changes are characteristic of acquired or sporadic diseases like cancer.[21]Both scenarios are investigated using similar molecular biology methods to detect DNA and RNA variations, although the interpretation and utility of the laboratory results often differ significantly.[22]

Fluorescent in situ hybridization (FISH), chromosomal microarray analysis (CMA), and cytogenetic analysis (karyotyping) can be used to detect gross mutations like whole- and large-scale gene deletions, duplications, or rearrangements. Conventional karyotyping identifies rearrangements over 5 DNA megabases.[23]FISH has a resolution of 100 kilobases to 1 megabase. Minor alterations, such as single-base substitutions, insertions, and deletions, are detectable with single-strand conformation polymorphism (SSCP) and sequence analysis through next-generation sequencing (NGS). NGS uses genomic DNA (gDNA) or complementary DNA (cDNA) and has 3 modalities: whole genomic DNA, targeted, and exome sequencing.[24]

Denaturing high-performance liquid chromatography (DHPLC) can detect small deletions and duplications. Multiplex ligation-dependent probe amplification (MLPA) extends the range of deletions and duplications detected, bridging the gap between FISH or cytogenetic analysis and HPLC. MLPA is particularly useful in identifying complete or single and multiexon deletions or duplications.[25][26]

Peripheral blood is the specimen required for FISH, MLPA, DHPLC, and sequencing.Amniotic fluid cells and, more recently, cell-free fetal DNAmay be used for noninvasive prenatal testing.[27]Ethylenediaminetetraacetic acid is the most commonly used anticoagulant for molecular-based testing. However, acid citrate dextrose (ACD) is an acceptable alternative in cases where cellular form and function must be preserved.

ACD A and ACD B are the only ACD tube designations recognized, differing only by their additive concentrations.[28]Both enhancewhite blood cell viability and recovery for several days after specimen collection, making them suitable for molecular diagnostic and cytogenetic testing.

FISH utilizes fluorescent DNA probes to target specific gene sequences in interphase or metaphase cells, enabling their visualization and detection. Housekeeping gene probes always serve as positive internal controls. The probe must be large enough to hybridize specifically with the target without impeding the hybridization process. Conventional FISH involves pipetting the hybridization mix onto the cytological sample and incubating them together.

The technique can be applied to suspended cells, cultured cells, and frozen or formalin-fixed paraffin-embedded tissue sections, with subsequent cell sorting for fluorescence signal separation.[29]Preserving nucleic acid integrity and cell morphology is necessary during sample fixation. The experimental FISH procedure includes several preparatory steps, the hybridization reaction itself, and the removal of unbound probes.[30]The probe may be directly labeled with fluorophores or targeted for fluorescent detection using labeled antibodies or similar substrates. Different tags may be used, and different targets may be detected in the same sample simultaneously (multi-color FISH). Tagging is performed in various ways, including nick translation or polymerase chain reaction (PCR) using tagged nucleotides (see Image. Polymerase Chain Reaction). Probes can vary from 20 to 30 nucleotides to much longer sequences.

Locus-specific probes provide insight into gene amplification, deletion, or normal copy number status. Dual-fusion probes are adept at identifying frequently translocated gene regions associated with cancer development. These probes target regions spanning the breakpoints of translocation partners. Intact green and red signals are determined when they are closer than one signal's width. Conversely, a break in the gene sequence results in separate green and red signals.[31]

Break-apart probes target 2 areas of a specific gene sequence, using a green fluorescent label on one end and a red fluorescent label on the other. Intact gene sequences typically produce a yellow signal, known as a fusion signal. Whole-chromosome probes consist of smaller probes, each binding to different sequences along a chromosome.[32]Multiple probes, labeled with fluorescent dyes, enable unique color labeling of each chromosome, creating a spectral karyotypea full-color chromosome map identifyingall chromosome pairs.[33]Whole-chromosome probes are useful for examining chromosomal abnormalities, such as translocations.

Chromosomal microarray (CMA) consists of thousands of tiny probes, each representing small DNA fragments from known locations on the 46 chromosomes. CMA detects imbalances in chromosomal material between patient and control DNA samples, identifying copy number differenceswhether gains (duplications) or losses (deletions)in specific DNA segments.[34]These differences pinpoint the cause of the patient's health condition based on the location and type of change detected.[35]

Denaturing high-performance liquid chromatography (DHPLC) relies on differential chromatography retention of DNA heteroduplexes post-denaturation and renaturation. DNA heteroduplex migration is influenced by both molecule length and melting temperature, which is crucial for test sensitivity. DHPLC typically compares 2 PCR products amplified from 2 genes: 1 wild type and 1 mutated. These PCR products can originate from either RNA (cDNA) or genomic DNA. The PCR products are denatured at 95 C and gradually reannealed by cooling from 95 C to 65 C before chromatography. A major advantage of this technology is that multiple samples can be pooled together for variant detection.[36]Sequencing detects single-base substitutions and small deletions and insertions in DNA fragments ranging from 80 to 1500 base pairs, with close to 100% accuracy within minutes.

When a mismatch is present, both the original homoduplexes and 2 heteroduplexes are simultaneously produced. The original homoduplexes form from the reannealing of perfectly matching sense and antisense strands (25% each). The heteroduplexes form from the reannealing of the sense strand of one homoduplex with the antisense strand of the other (also 25% each). Heteroduplexes denature more extensively than homoduplexes, resulting in earlier elution from the chromatography column. The separation of all 4 species is based on their differences in stacking interactions with the chromatography column (solid phase). More detailed theoretical explanations of DHPLC are available in the literature.[37]

MLPA utilizes genomic DNA samples, with specific MLPA probes hybridizing with denatured genomic DNA. These probes are uniquely designed to hybridize adjacent to each other on the target DNA region and confer a distinct length to each amplified MLPA probe pair. Detection and quantification occur via capillary electrophoresis.[38]All MLPA probes are amplified using the same primer pair, with the abundance of each fragment proportional to its target's copy number in the sample.

NGS amplifies DNA with random priming, providing a genome-wide view of the patient's genetic background through millions of reads. Library generation begins with nucleic acid fragmentation, representing the individual's entire genome or transcriptome. Whole-exome sequencing uses cDNA fragments, whereas the whole-genome modality includes complete genomic DNA. Fragments join using enriched sequence adaptors. Only some genes (gene panel) are analyzed in targeted libraries. Fragments hybridize with cDNA fragments for the region or genes of interest and are specifically enriched.[39]During sequencing, nucleotide addition is detected by fluorescent dyes or pH changes from hydrogen ion release during DNA polymerization.[40]

Sanger sequencing begins with PCR-based target DNA amplification, followed by removing excess deoxynucleotide triphosphates (dNTPs) and PCR primers. The Sanger method has 99.99% base accuracy and is thus the "gold standard" for validating DNA sequences, including those from NGS. The test's stepsinclude denaturing the double-stranded DNA (dsDNA) into 2 single-stranded DNA (ssDNA), attaching a primer corresponding to one end of the sequence, and sequencing 4 polymerase solutions with 4 dNTPs. Only one type of ddNTP is incorporated, initiating DNA synthesis until termination. The resulting DNA fragments are denatured into ssDNA.

Denatured fragments undergo gel electrophoresis for sequence determination. DNA polymerase synthesizes DNA only in the 5 to 3 direction, initiating at a provided primer. Each terminal ddNTP corresponds to a specific nucleotide in the original sequence. For example, the shortest fragment must terminate at the first nucleotide from the 5 end, the second-shortest fragment must terminate at the second nucleotide from the 5 end, and so on. Reading gel bands from smallest to largest reveals the 5 to 3 sequence of the original DNA strand.[41]

In manual Sanger sequencing, the user reads all 4 gel lanes simultaneously, moving from bottom to top to identify the terminal ddNTP for each band. For instance, if the bottom band is found in the ddGTP column, then the smallest PCR fragment terminates with ddGTP, and the first nucleotide from the 5 end of the original sequence has a guanine (G) base.[42]Automated Sanger sequencing employs a computer to read each capillary gel band sequentially, using fluorescence to determine the terminal ddNTP identity. Laser activation of fluorescent tags emits light, detected by the computer, with each ddNTP tagged with a unique fluorescent label. The output is a chromatogram displaying fluorescent peaks corresponding to each nucleotide along the template DNA's length.[43]

Third-generation sequencing enables sequencing long DNA or RNA stretches without fragmentation. Single strands of DNA or RNA are directed through protein nanopores, with nucleotide bases distinguished by characteristic changes in electric current to determine the sequence.[44]Compared to 2nd-generation sequencing, 3rd-generation sequencing requires minimal sample preprocessing, enabling the design of smaller and more portable equipment.[45]

Molecular genetic testing has distinct indications, differing from traditional clinical and molecular biological testing used for diagnosing other diseases.[46]This modalitys applications encompass newborn screening, diagnostic testing for genetic or chromosomal conditions, carrier testing, prenatal testing, predictive and presymptomatic testing for adult-onset disorders, and forensic testing for legal identification purposes.[47]

FISH is employed for patients with a family history of known deletions and has been utilized to detect deletions in single blastomeres during preimplantation genetic diagnosis. FISH tests use gene-specific probe panels to investigate deletions, amplifications, and translocations in hematologic and solid tumors. FISH can also identify intracellular microorganisms and parasites.

CMA is recommended for individuals lacking specific clinical indicators to identify genetic or nongenetic causes of intellectual disability, developmental delay, autism spectrum disorder, or multiple congenital anomalies.[48]CMA can be helpful if prenatal structural anomalies are linked to particular microdeletions or microduplications. This modality can also evaluate copy number variants in cases of de novo balanced rearrangements or marker chromosomes.[49]

MLPA has diverse applications, such as mutation detection, single nucleotide polymorphisms (SNP) analysis, DNA methylation analysis, mRNA quantification, chromosomal characterization, gene copy number detection, and identification of duplications and deletions in cancer predisposition genes like BRCA1, BRCA2, hMLH1, and hMSH2. MLPA also holds promise for prenatal diagnosis, both invasive and noninvasive.[50]

DHPLC is well-suited for scanning genes for novel mutations and analyzing large sample sizes cost-effectively. This test is also useful for genotyping specific mutations or polymorphisms. DHPLC offers various applications beyond detecting genetic variants, including size-based double-strand DNA separation, single-strand DNA separation, and DNA purification analysis.[51]

NGS rapidly sequences whole genomes and target regions, employs RNA sequencing to identify novel RNA variants and splice sites, quantifies mRNAs for gene expression analysis, and analyzes epigenetic factors like DNA methylation and DNA-protein interactions. Sequence cancer samples study rare somatic variant tumor subclones and identify novel pathogens. Sanger sequencing, or the "chain termination method," determines DNA nucleotide sequences.

FISH swiftly diagnoses common fetal aneuploidies but with reduced sensitivity compared to cytogenetic analysis. FISH cannot identify cytogenetic abnormalities beyond the most common ones, such as translocations, inversions, and markers. DHPLC detects single nucleotide changes, small deletions, or insertions requiring subsequent confirmation by sequencing. This method identifies unknown mutations, making it advantageous for diseases with a high proportion of de novo mutations. Neurofibromatosis type 1 (NF1) is an example, as approximately 50% of cases arise from new mutations. CMAs are first-tier tests for developmental delays, intellectual disabilities, autism spectrum disorders, or multiple congenital disabilities, replacing karyotyping.

MLPA detects gene abnormalities, particularly small deletions in diseases like multiple endocrine neoplasia type 1 (MEN1partial or complete deletion). MLPA can also assess methylation alterations, such as in pseudohypoparathyroidism 1b (PHP1b), where deletion of 1 or 4 of four differentially methylated regions is common.

NGS generates millions of sequences, which are then processed, analyzed, and interpreted to identify variants. Bioinformatics analysis begins with raw data generated by nucleotide incorporation signal detection. Read quality is evaluated during primary data analysis. Sequences are aligned or mapped against a reference genome, with computational algorithms searching for the best match for each read while allowing for some mismatches to detect genetic variants.[52]

Sanger sequencing is reliable in detecting point mutations, small deletions, or duplications. This method has a long history of use across various settings, including tumor mutational spectrum analysis and diagnostic testing for constitutional variants. Primers can cover multiple regions (amplicons) or any desired region size.

The increasing demand for genetic testing has led to greater availability. Ensuring uniformity and standardization in communicating the complex results to referring clinicians is essential. Failure to include pertinent information is considered a deficiency in the molecular pathology laboratory accreditation inspection.[53]All molecular genetic laboratories offering clinical testing should be accredited according to the Clinical Laboratory Improvement Amendments and actively participate in proficiency testing.[54]

A comprehensive genetic report must include essential patient details such as name, medical record number or birth date, sex, and ethnicity. The report should also specify the type of specimen received, identification number, laboratory test requested, the performing laboratorys name and address, and referring healthcare professional or hospital. The date of the report, analytic result interpretation using standard nomenclature, detailed method description (including literature citations if applicable), and assay sensitivity and specificity should be provided. For example, sensitivity and specificity should be reported regarding the number of variants analyzed, the proportion of variants not detected, and the possibility of genetic heterogeneity and recombination.[55]Reports from clinical DNA laboratories should include a disclaimer due to the prevalence of laboratory-developed tests (LDTs) or procedures (LDPs) designed, developed, and validated internally by each laboratory but remain unapproved by the FDA.[56]

Fluorescent tags binding to chromosomes reveal chromosomal abnormalities in FISH. MLPA detects copy number variations by correlating peak intensity during capillary electrophoresis with sample copy numbers. An MLPA probe's amplification signals the presence of a mutation in the sample.

An MLPA test can yield two outcomes:

DHPLC detects mutations by identifying heteroduplexes compared to the reference genome in the same sample. NGS identifies various genetic variants, including single nucleotides, small insertions or deletions, and some structural variants, but their role in the disease is not implied. Clinical analysis and assessment of the pathological potential of detected variants require consideration in different contexts.[58]Sanger sequencing results interpretation depends on the target DNA strand and primer availability. If strand A is of interest but the primer suits strand B better, the output matches strand A. Conversely, if the primer suits strand A better, the output aligns with strand B, necessitating conversion back to strand A.

FISH probe specificity prevents unintended hybridization with nontarget genes. Some FISH preparations may exhibit autofluorescence, necessitating thorough cell washing to remove fluorescent residues and reduce background fluorescence.

MPLA has limitations, including its ability to detect only known mutations designed into probes, making gene rearrangements like inversions and translocations undetectable. Sample purity is essential as contaminants such as phenol can interfere with the ligation step. MLPA may yield false positive or negative results due to rare sequence variants in target regions detected by probes. Reduced probe binding efficiency from point mutations or polymorphisms candiminishthe relative peak areas height. Confirmation of single exon deletions detected by MLPA is thus recommended using other methods like multiplex PCR or sequencing.[59]

DHPLC sensitivity relies on melting temperature. Computational algorithms can predict the melting temperature, and the procedure typically involves at least 2 melting temperatures for increased sensitivity. CMA does not detect point mutations, small DNA segment changes (eg, in Fragile X syndrome), or balanced chromosomal rearrangements (eg, balanced translocations, inversions).

NGS technologies continue to evolve to address various challenges. Some large sequencers can detect large insertions, duplications, and deletions, while sequencing long homopolymer regions remains problematic. However, establishing the infrastructure and expertise for data analysis remains a significant challenge in clinical settings. The primary limitation of implementing NGS in clinical settings is the requirement for adequate infrastructure, including computational resources, storage capacity, and skilled personnel for comprehensive data analysis and interpretation.

Despite automation, Sanger sequencing remains labor-intensive, time-consuming, and expensive, relying on specialized equipment. Sanger sequencing exhibits reduced sensitivity in detecting point mutations when 20% of mutant DNA is of a wild-type background. Additionally, it lacks quantifiability, making it impossible to differentiate mutation prevalence accurately based solely on peak sizes, necessitating supplementary testing approaches.

Peripheral blood collection via venipuncture infrequently leads to serious complications. Some patients, especially children, may experience hematomas, pain, and fear, which are expected. In contrast, procedures like amniocentesis are more invasive, thus posing more serious risks such as infection, preterm delivery, respiratory distress, trauma, and alloimmunization, though these complications are also infrequent.[60]Genetic tests using NGS of free-cell DNA from maternal peripheral blood offer an alternative to diagnosis using amniocentesis fluid.[61]

Molecular testing may give rise to legal, medical, psychological, and ethical issues besides the sampling procedures potential complications.[62]While molecular testing primarily aims to demonstrate a genetic trait associated with a disease, the current recommendation is to integrate the results into genetic counseling.[63]

Genetic counseling, led by a team including genetic counselors and other professionals, begins with clinically identifying suspected diseases to guide molecular testing. Patients are informed about the testing procedure, potential results, and legal considerations like informed consent, particularly for children.[64]Patient education is integral to this process.

NGS technologies applied to genetic counseling yield complex results surpassing traditional tests, necessitating informed patient discussions due to the considerable information and ethical implications involved.[65]Laboratories conducting molecular genetic tests should address preexamination, examination, and postexamination considerations, tailoring methodology and interpretation to each test's indication, application, and ethical implications.

Any permanent alteration in a gene's nucleotide sequence compared to a reference genome is deemed a genetic change or mutation. Variants identified through a tiered protocol must undergo sequencing confirmation, and their role in disease pathology must be assessed. Genetic testing may reveal variants classified as benign, likely benign, pathogenic, likely pathogenic, or of uncertain significance.[66]Variants must be rigorously classified based on various types of evidencepopulation, computational, functional, or segregation datato determine clinical significance.[67]

The American College of Medical Genetics and Genomics recommends this nomenclature and classification for genetic test findings, covering genotyping, single genes, panels, exomes, and genomes. NGS applications have deepened our understanding of genetic diseases and led to the discovery of variants requiring further study of their disease implications.[68]Interprofessional collaboration is essential for leveraging genetic tests for patient benefit, withan expertpanel advocating for results interpretation by a board-certified geneticist.[69]

Molecular genetic testing advanced significantly with PCR and NGS, providing genome-wide data.[70]Multidisciplinary teams collaborate to integrate various testing methods with clinical, pathological, functional, computational, ethical, and social aspects of diseases for patient benefit.[71]

Polymerase Chain Reaction. This diagram shows the polymerase chain reaction steps. Enzoklop,Public Domain via Wikimedia Commons

Trisomy 21 on G-Banded Chromosome Studies. This karyogram depicts trisomy 21 resulting from an inherited Robertsonian translocation between chromosomes 14 and 21. The infant's father was a carrier of the translocation in a balanced form. Crotwell PL, (more...)

Disclosure: Cecilia Ishida declares no relevant financial relationships with ineligible companies.

Disclosure: Muhammad Zubair declares no relevant financial relationships with ineligible companies.

Disclosure: Vikas Gupta declares no relevant financial relationships with ineligible companies.

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Molecular Genetics Testing - StatPearls - NCBI Bookshelf

Genetics is the study of genes, genetic variation, and heredity in living organisms. This online textbook covers major topics in molecular genetics in a problems-based approach. It grew out of teaching a course for upper level undergraduates and graduate students at the Pennsylvania State University.

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Working with Molecular Genetics (Hardison) - Biology LibreTexts

The complex molecular underpinnings of genetic and rare diseases offer a promising avenue for scientific exploration and innovation. This research topic explores the intricate molecular mechanisms driving these conditions, underlining the latest developments in diagnostic methodologies and therapeutic approaches. Due to the rapid advancement in molecular diagnostics, including Next-Generation Sequencing, our insights into rare and genetic diseases have expanded significantly.

Through this research topic, our aim is to uncover genetic and molecular mechanisms driving the onset and progression of genetic and rare diseases, with a particular focus on unraveling actionable therapeutic targets. By integrating advanced molecular biology methods, including Next-Generation Sequencing, CRISPR, and other cutting-edge technologies, this topic emphasizes the development of novel therapeutic approaches. The goal is to translate these molecular insights into innovative, personalized therapies that address the specific challenges of genetic and rare diseases, ultimately improving patient outcomes and advancing the field of precision medicine.

This Research Topic addresses significant challenges in accurately diagnosing and effectively treating genetic and rare diseases. Despite advances in molecular diagnostics, many of these conditions remain underdiagnosed or misdiagnosed, delaying crucial interventions. Recent developments in technologies like Next-Generation Sequencing have revolutionized our ability to detect genetic anomalies, but there is still a need to bridge the gap between these diagnostics and targeted therapeutic strategies. This topic seeks to explore how integrating advanced molecular tools with therapeutic innovations can lead to more precise and personalized treatments, ultimately improving outcomes for patients with genetic and rare diseases.

We welcome submissions of original research articles, in-depth reviews, case studies, and perspective pieces that advance the understanding of the genetic and molecular foundations of genetic and rare diseases. Contributions that explore novel diagnostic tools, therapeutic strategies, and translational research are particularly encouraged.

This Research Topic will cover a wide range of themes related to genetic and rare diseases, including but not limited to:

Identification and characterization of novel genetic mutations and their clinical implications;

Advances in molecular diagnostic technologies, including Next-Generation Sequencing and multi-omics approaches;

Development of targeted therapies and personalized treatment strategies for rare and genetic disorders;

Translational research bridging molecular diagnostics and therapeutic applications;

Ethical and clinical considerations in the treatment of genetic and rare diseases.

Keywords:Rare Diseases, Genetic Diseases, Next-Generation Sequencing, Molecular Diagnostics, Clinical Genomics

Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

Through this research topic, our aim is to uncover genetic and molecular mechanisms driving the onset and progression of genetic and rare diseases, with a particular focus on unraveling actionable therapeutic targets. By integrating advanced molecular biology methods, including Next-Generation Sequencing, CRISPR, and other cutting-edge technologies, this topic emphasizes the development of novel therapeutic approaches. The goal is to translate these molecular insights into innovative, personalized therapies that address the specific challenges of genetic and rare diseases, ultimately improving patient outcomes and advancing the field of precision medicine.

This Research Topic addresses significant challenges in accurately diagnosing and effectively treating genetic and rare diseases. Despite advances in molecular diagnostics, many of these conditions remain underdiagnosed or misdiagnosed, delaying crucial interventions. Recent developments in technologies like Next-Generation Sequencing have revolutionized our ability to detect genetic anomalies, but there is still a need to bridge the gap between these diagnostics and targeted therapeutic strategies. This topic seeks to explore how integrating advanced molecular tools with therapeutic innovations can lead to more precise and personalized treatments, ultimately improving outcomes for patients with genetic and rare diseases.

We welcome submissions of original research articles, in-depth reviews, case studies, and perspective pieces that advance the understanding of the genetic and molecular foundations of genetic and rare diseases. Contributions that explore novel diagnostic tools, therapeutic strategies, and translational research are particularly encouraged.

This Research Topic will cover a wide range of themes related to genetic and rare diseases, including but not limited to:

Identification and characterization of novel genetic mutations and their clinical implications;

Advances in molecular diagnostic technologies, including Next-Generation Sequencing and multi-omics approaches;

Development of targeted therapies and personalized treatment strategies for rare and genetic disorders;

Translational research bridging molecular diagnostics and therapeutic applications;

Ethical and clinical considerations in the treatment of genetic and rare diseases.

Keywords:Rare Diseases, Genetic Diseases, Next-Generation Sequencing, Molecular Diagnostics, Clinical Genomics

Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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Molecular Underpinnings of Genetic and Rare Diseases: From ... - Frontiers

The high heritability of schizophrenia has stimulated much work aimed at identifying susceptibility genes using positional genetics. However, difficulties in obtaining clear replicated linkages have led to the skepticism that such approaches would ever be successful. Fortunately, there are now signs of real progress. Several strong and well-established linkages have emerged. Three of the best ...

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The molecular genetics of schizophrenia: New findings promise new insights.

Genetics is the study of the inheritance and variation of biological traits. We have previously noted that it is possible to conduct genetic research without directly studying DNA. Indeed some of the greatest geneticists had no special knowledge of DNA at all, but relied instead on analysis of phenotypes, inheritance patterns, and their ratios in carefully designed crosses.

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8: Techniques of Molecular Genetics - Biology LibreTexts

Genes and Proteins

Since the rediscovery of Mendels work in 1900, the definition of the gene has progressed from an abstract unit of heredity to a tangible molecular entity capable of replication, transcription, translation, and mutation. Genes are composed of DNA and are linearly arranged on chromosomes. Some genes encode structural and regulatory RNAs. There is increasing evidence from research that profiles the transcriptome of cells (the complete set all RNA transcripts present in a cell) that these may be the largest classes of RNAs produced by eukaryotic cells, far outnumbering the protein-encoding messenger RNAs (mRNAs), but the 20,000 protein-encoding genes typically found in animal cells, and the 30,o00 protein-encoding genes typically found in plant cells, nonetheless have huge impacts on cellular functioning.

Protein-encoding genes specify the sequences of amino acids, which are the building blocks of proteins. In turn, proteins are responsible for orchestrating nearly every function of the cell. Both protein-encoding genes and the proteins that are their gene products are absolutely essential to life as we know it.

Replication, Transcription, and Translation are the three main processes used by all cells to maintain their genetic information and to convert the genetic information encoded in DNA into gene products, which are either RNAs or proteins, depending on the gene. In eukaryotic cells, or those cells that have a nucleus, replication and transcription take place within the nucleus while translation takes place outside of the nucleus in cytoplasm. In prokaryotic cells, or those cells that do not have a nucleus, all three processes occur in the cytoplasm.

Replication is the basis for biological inheritance. It copies a cells DNA. The enzyme DNA polymerase copies a single parental double-stranded DNA molecule into two daughter double-stranded DNA molecules. Transcription makes RNA from DNA. The enzyme RNA polymerase creates an RNA molecule that is complementary to a gene-encoding stretch of DNA. Translation makes protein from mRNA. The ribosome generates a polypeptide chain of amino acids using mRNA as a template. The polypeptide chain folds up to become a protein.

The central dogma of molecular biology describes the flow of genetic information in cells from DNA to messenger RNA (mRNA) to protein. It states that genes specify the sequence of mRNA molecules, which in turn specify the sequence of proteins. Because the information stored in DNA is so central to cellular function, the cell keeps the DNA protected and copies it in the form of RNA. An enzyme adds one nucleotide to the mRNA strand for every nucleotide it reads in the DNA strand. The translation of this information to a protein is more complex because three mRNA nucleotides correspond to one amino acid in the polypeptide sequence.

Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that enzymes can convert back and forth from DNA to RNA. During transcription, a DNA sequence is read by RNA polymerase, which produces a complementary, antiparallel RNA strand. Unlike DNA replication, transcription results in an RNA complement that substitutes the RNA uracil (U) in all instances where the DNA thymine (T) would have occurred. Transcription is the first step in gene expression. The stretch of DNA transcribed into an RNA molecule is called a transcript. Some transcripts are used as structural or regulatory RNAs, and others encode one or more proteins. If the transcribed gene encodes a protein, the result of transcription is messenger RNA (mRNA), which will then be used to create that protein in the process of translation.

Translation is the process by which mRNA is decoded and translated to produce a polypeptide sequence, otherwise known as a protein. This method of synthesizing proteins is directed by the mRNA and accomplished with the help of a ribosome, a large complex of ribosomal RNAs (rRNAs) and proteins. In translation, a cell decodes the mRNAs genetic message and assembles the brand-new polypeptide chain. Transfer RNA, or tRNA, translates the sequence of codons on the mRNA strand. The main function of tRNA is to transfer a free amino acid from the cytoplasm to a ribosome, where it is attached to the growing polypeptide chain. tRNAs continue to add amino acids to the growing end of the polypeptide chain until they reach a stop codon on the mRNA. The ribosome then releases the completed protein into the cell.

DNA to protein: This interactive shows the process of DNA code being translated to a protein from start to finish!

The genetic code is degenerate as there are 64 possible nucleotide triplets (43), which is far more than the number of amino acids. These nucleotide triplets are called codons; they instruct the addition of a specific amino acid to a polypeptide chain. Sixty-one of the codons encode twenty different amino acids. Most of these amino acids can be encoded by more than one codon. Three of the 64 codons terminate protein synthesis and release the polypeptide from the translation machinery. These triplets are called stop codons. The stop codon UGA is sometimes used to encode a 21st amino acid called selenocysteine (Sec), but only if the mRNA additionally contains a specific sequence of nucleotides called a selenocysteine insertion sequence (SECIS). The stop codon UAG is sometimes used by a few species of microorganisms to encode a 22nd amino acid called pyrrolysine (Pyl). The codon AUG, also has a special function. In addition to specifying the amino acid methionine, it also serves as the start codon to initiate translation. The reading frame for translation is set by the AUG start codon.

The genetic code is universal. With a few exceptions, virtually all species use the same genetic code for protein synthesis. The universal nature of the genetic code is powerful evidence that all of life on Earth shares a common origin.

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1.5: Molecular Genetics - Biology LibreTexts

Abstract

Genetics have undoubtedly become an integral part of biomedical science and clinical practice, with important implications in deciphering disease pathogenesis and progression, identifying diagnostic and prognostic markers, as well as designing better targeted treatments. The exponential growth of our understanding of different genetic concepts is paralleled by a growing list of genetic terminology that can easily intimidate the unfamiliar reader. Rendering genetics incomprehensible to the clinician however, defeats the very essence of genetic research: its utilization for combating disease and improving quality of life. Herein we attempt to correct this notion by presenting the basic genetic concepts along with their usefulness in the cardiology clinic. Bringing genetics closer to the clinician will enable its harmonious incorporation into clinical care, thus not only restoring our perception of its simple and elegant nature, but importantly ensuring the maximal benefit for our patients.

All inheritable traits of living organisms are determined by their genetic material, the genome, a long nucleic acid called deoxyribonucleic acid (DNA). The DNA consists of 3109 nucleotides. Each nucleotide is made up of a sugar (deoxyribose), a nitrogenous base (adenine (A), guanine (G), cytosine (C) or thymine (T)) and a phosphate group () [1,2]. The four nitrogenous bases are divided into two groups: purines (including A and G) have two joined heterocyclinc rings and pyrimides (including C and T) have a single heterocyclic ring. Successive sugar and phosphate residues are linked by covalent phosphodiester bonds, forming the backbone of the DNA molecule and a nitrogenous base is attached to each sugar. The stability of DNA is primarily dependent on the strong covalent bonds that connect the constituent atoms of its linear backbone, and also on a number of weak non-covalent bonds that exist. Meanwhile, because of the phosphate group charges present in each nucleotide, DNA is negatively charged and therefore highly soluble in water.

The chemical structure of a nucleotide including the phosphate (yellow), the sugar (deoxyribose in green) and adenine as the nitrogenous base (pink).

The DNA structure is a double helix, in which two DNA molecules are held together by weak hydrogen bonds [37]. Hydrogen bonding occurs between laterally opposed bases, of the two strands according to Watson-Crick rules: A specifically binds to T, and G to C. The two strands are therefore complementary [8]. As the phosphodiester bonds link carbon atoms number 3 and number 5 of successive sugar residues, the end of each DNA strand will have a terminal sugar residue where carbon atom number 5 is not linked to a neighboring sugar residue, and is therefore called 5 end. The other end of the molecule is similarly called 3 end. The two DNA strands are antiparallel because they always associate (anneal) in such a way that the 53 direction of one DNA strand is the opposite to that of its partner. To describe a DNA sequence, the sequence of bases of one strand only, are usually provided, and are provided in the 53 direction. This is the direction of DNA replication as well as transcription.

The human DNA is estimated to be approximately 2 m long. In order for it to fit in the 10 m nucleus of human cells it is imperative that it is tightly folded. The DNA double helix is therefore subjected to at least two levels of coiling: the first involving coiling around a central core of eight histone proteins, resulting in units called nucleosomes, which are connected by spacer DNA; and the second involving coiling of this string of nucleosomes into a chromatin fiber [3]. During the different phases of the cell cycle, the DNA varies in the extent of its condensation. For example, during interphase the chromatin fibers are organized into long loops, whereas in metaphase chromosomes, the DNA is compacted to about 1/10,000 of its stretched out length. In humans there are 24 different chromosomes, namely 122 autosomes, and sex chromosomes X and Y [9]. Since humans are diploid organisms, our DNA is found in two copies, one inherited from each parent, and is folded into 46 chromosomes. Among the major DNA sequence elements of each chromosome are: the centromeres (constriction site where sister chromatics are joined and chromosomes link to the mitotic spindle), the telomeres (structures capping the ends of chromosomes) and the origins of replication (where DNA replication begins). Chromatin is encountered in extended (euchromatin) or highly condensed (heterochromatin) states, which in turn affect the transcriptional status of the corresponding DNA regions (being active or inactive, respectively) [10]. Under the light microscope, these regions appear as light and dark bands of metaphase chromosomes ().

Diagrammatical representation of the human karyotype of haploid chromosome set with X and Y as the sex chromosome complement. The alternating light and dark bands are characteristic of each chromosome in standard G-banding karyotype, and they represent euchromatic and heterochromatic regions, respectively.

Genomic DNA contains coding as well as non-coding regions. The non-coding regions are involved in DNA folding, chromosome formation, chromatin organization within the nucleus, regulation of transcription and more [1114]. The coding regions are responsible for the transcription of RNA molecules and ultimately protein synthesis.

The genes are stretches of DNA that code for polypeptides. Specifically, genes contain regulatory and coding regions, which regulate their transcription or code for the polypeptide product, respectively. A key regulatory region is the promoter, where the transcription machinery binds for transcription to be initiated. Other possible regulatory regions include enhancers, which regulate gene expression in different tissues or cells, and can be found upstream or downstream of the coding region, as far as several thousand bases. The coding regions are represented by exons, whose size and number varies among different genes. Interspersed between gene exons, there are non-coding sequences named introns, which tend to make up the largest percentage of a gene. The human genome is estimated to contain approximately 20,000 different genes [15]. Interestingly, it is estimated that 80% of the human genome is expressed, yet only 2% is coding for proteins [16].

The central dogma of molecular biology was first stated in 1958 and re-stated in 1970 by Francis Crick [17,18]. According to this dogma there are three major classes of biopolymers: DNA, RNA and protein, and three classes of direct transfer of information that can occur between these biopolymers: general transfers, special transfers and unknown transfers. Of these, only the general transfers are believed to occur normally in most cells and they involve DNA replication to DNA, DNA transcription to mRNA and mRNA translation to proteins ().

The central dogma of molecular biology, as it currently applies in most cells (general transfers = black),or under specific conditions (in some viruses and in vitro: special transfers = grey).

The transfer of information from the DNA to the protein level is achieved step-wise and starts with the transcription of a gene to mRNA. Specifically, the transcription machinery (including RNA polymerase and a variety of transcription factors) binds to the gene promoter, the double helix opens in that location and a single strand primary mRNA molecule (hn-RNA), complementary to that gene sequence, is synthesized base by base () [19]. RNA as opposed to DNA, is a single strand nucleic acid containing ribose instead of deoxyribose and uracil instead of thymine. The heterogenous (hn)-RNA molecules go through a series of processing steps including a 5 cap, a poly-A (50250 adenine molecules and a 70kDa protein) tail at the 3 end and splicing, to remove the intronic sequences () [2023]. Alternative splicing can also occur, which removes certain exons and contributes to the diversity of proteins any single gene can produce [24].

During transcription the transcription machinery (including RNA polymerase and a variety of transcription factors) binds to the gene promoter, the double helix opens in that location and a single strand primary mRNA molecule (hn-RNA),complementary to that gene sequence, is synthesized base by base.

The promoter and enhancer elements of each gene are involved in gene transcription to precursor mRNA (hn-RNA) molecules which are then appropriately processed to give mature mRNA.

The mature mRNA molecules can be translated to proteins [25]. This process takes place in the cytoplasm with the aid of ribosomes, which are complexes of RNAs and proteins called ribonucleoproteins. The ribosomes are divided into two subunits: the smaller subunit binds to the mRNA, while the larger subunit binds to the tRNA which carries the amino acids. When a ribosome finishes reading a mRNA, these two subunits split apart. In particular, ribosomes bind mRNA and read through it as triplet codons, usually starting with an AUG triplet (initiation codon) downstream of the ribosome binding site. For each codon, the ribosome, with the aid of initiation and elongation factors, recruits a complementary tRNA molecule, which in turn carries a specific amino acid. Each codon codes for a specific amino acid as shown in . As the amino acids are linked into the growing peptide chain, they begin folding into the correct conformation. The translation process ends with the stop codons UAA, UGA or UAG. The nascent polypeptide chain is then released from the ribosome as a mature protein [25]. In some cases the new polypeptide chain requires additional processing to make a mature protein. Mature proteins in turn can be subjected to a range of post-translational modifications. Their ultimate roles in cell physiology can be highly variable including cytoarchitecture, enzymatic activity, intracellular signalling, transportation, communication etc.

Genetic variation refers to genetic difference between individuals within or between different populations. This variation is what renders each individual unique in its phenotypic characteristics. Genetic variation occurs on many different scales, ranging from gross alterations in the human karyotype to single nucleotide changes. These variations can be divided in polymorphisms and mutations.

Polymorphisms are defined as variants found in >1% of the general population [26]. Due to their high frequency they are considered unlikely to be causative of genetic disease. They can however, together with other genetic and environmental factors, affect disease predisposition, disease progression or response to treatments (e.g. [27]). Three common types of polymorphisms are the single nucleotide polymorphisms (SNPs), small insertions/deletions (indels) and the large-scale copy number polymorphisms (CNPs or CNVs). SNPs are single base changes that occur on average about every 1000 bases in the genome. Their distribution is not homogenous and they occur more frequently in non-coding regions where there is less selective pressure () [28,29]. Most SNPs are neutral; yet 35% are thought to have a functional role, i.e. affect the phenotype of the individual carrying them. Depending on their effect at the protein level, SNPs can be characterized as synonymous (coding for the same amino acid as the wild type DNA sequence) or non-synonymous (coding for a different amino acid than the wild type DNA sequence) [29]. Indels are small insertions or deletions ranging from 1 to 10,000 bp in length, although the majority involves only a few nucleotides [30,31]. They are considered the second most common form of variation in the human genome following SNPs, with over 3 million short indels listed in public databases. CNVs are variations in the number of copies of DNA regions. They can involve loss of one or both copies of a region of DNA, or the presence of more than two copies of this region. They can arise from DNA deletions, amplifications, inversions or insertions and their size can range from 1 kb (1,000 bases) to several megabases [32]. SNPs, indels and CNVs can either be inherited or arise de novo.

A Single-Nucleotide DNA Polymorphism (SNP) is defined as a single DNA variation detected when a single nucleotide in the genome (or other common sequence) is different between species or paired chromosomes in an individual. In this case there is a substitution of a C (Cytosine) in a T (Tymine) which causes the change of a G (Guanine) in a A (Adenine) in the complementary DNA strand.

Mutations on the other hand, are rare (by some defined as variations with <1% frequency in the general population, although there are many exceptions to this rule) changes in the DNA sequence that can change the resulting protein, impair or inhibit the expression of the gene, or leave both the gene function and protein levels/structure unaffected. Although a variety of definitions have been considered over the years, for most scientists mutation has become synonymous with disease. They can arise during DNA replication or as a result of DNA damage through environmental agents including sunlight, cigarette smoke and radiation. A variety of different types of mutations exist and the terminology used to describe them is based on their effect either on DNA structure, on protein product function, or on the fitness of the individual carrying them.

In terms of DNA structure modification, mutations can be categorized as:

A) point mutations in which a single nucleotide is changed for a different one (). These are divided into missense mutations (meaning that when translated this DNA sequence leads to the incorporation of a different amino acid into the produced protein, with possible implications in the protein function), nonsense mutations (where the new nucleotide changes the sequence so that a stop codon is formed earlier than in the normal sequence and therefore the produced protein is truncated), silent mutations (where the nucleotide change does not affect the amino acid in the corresponding position of the produced protein, and therefore the final protein product remains unaltered), and splice-site mutations (which affects the splice site invariant donor or acceptor dinucleotides (5GT or 3AG).

Different types of mutation and possible conseuquence on protein function:A) missense mutation; B) nonsense mutation; C) deletion; D) inversion.

B) insertions in which one or more nucleotides are inserted in the normal DNA sequence, therefore disrupting it. This can have a moderate or severe effect on the corresponding mutant protein product. For example it can affect the splicing or the reading frame ( frame-shift mutations), therefore leading an incorrect reading of all the downstream nucleotide triplets and consequently their translation to a significantly different and/or truncated amino acid sequence.

C) deletions in which one or more nucleotides are deleted from the normal DNA sequence (). As in the case of insertions this can lead to minor (e.g. single amino acid changes) or major protein defects (e.g. reading frame modifications with implications for the entire downstream amino acid sequence of the mutant protein). When larger chromosomal regions are deleted, multiple genes can be lost and/or previously distant DNA sequences can now be juxtaposed (such juxtapositions can lead, for example, to the production of abnormal proteins containing sequences from different genes that have now been merged or abnormal expression of otherwise normal proteins by deletions affecting their upstream regulatory regions).

D) amplifications leading to multiple copies of chromosomal regions and consequently to an increased number of copies of the genes located within them and increased levels of the corresponding proteins.

E) inversions involving the reversal of the orientation of a DNA segment, with variable implications for the protein product, similar to the ones described above ().

F) translocations where regions from non-homologous chromosomes are interchanged.

Mutations can affect the expression of a transcript and its corresponding protein, or modify the structure of the resulting protein therefore impairing its function [33]. Depending on their functional effect, mutations can be classified as dominant negative (the mutant gene product acts antagonistically to the wild-type allele), gain-of-function (the mutant gene product gains a new and abnormal function), and loss-of-function (the mutant gene product has less or no function). Loss-of-function mutations can be associated with haploinsufficiency, a common occurrence in the molecular cardiomyopathy setting.

Haploinsufficiency occurs when the gene product of one of the two alleles in an individual is lost due to a DNA deletion or to instability/degradation of the mutant protein. Other terms used to describe the effect of a mutation on the fitness of the carrier are: harmful or deleterious mutations (decreases the fitness of the carrier), beneficial or advantageous mutations (increases the fitness of the carrier), and lethal mutations (leading to the death of the individual carrying them).

In the field of cardiovascular genetics, when a new genetic variant is identified a common occurrence given the large number of genes and different variants thereof being screened it is crucial to first determine whether it represents a benign polymorphism or a pathogenic mutation. Identifying pathogenic mutations enables the characterization of the molecular mechanisms of pathogenesis, and more importantly for the clinical setting, it allows the development of genetic tests for mutation detection in other family members (including pre-symptomatically) as well as unrelated patients with similar phenotypes (see section on Cardiovascular genetics in clinical practice).

The Clinical Molecular Genetics Society1 and the American College of Medical Genetics2 have issued guidelines to facilitate the determination of the potential pathogenic role of a novel/unclassified variant (). The Human Gene Mutation Database,3 along with locus-specific or disease-specific mutation databases, are valuable resources for first deciphering whether a detected genetic variant represents a known mutation. The databases Online Mendelian Inheritance in Man,4 dbSNP5 and Ensembl,6 along with thorough searches of the literature via PubMED, Google Scholar, Scopus or the Web of Science, can also provide valuable information. From thereon carefully matched controls need to be included in the study populations, co-occurrence with known (in trans) deleterious mutations in the same gene needs to be ruled out, co-segregation with the disease in the family represents useful information, and occurrence of the novel variant concurrent with the incidence of a sporadic disease can be a strong indicator. Bioinformatically, it is important to determine if the unclassified variant leads to an animo acid change and how different the biophysical properties of the new amino acid are: the greater the difference, the higher the likelihood to possess a pathogenic role. Similarly, the more conserved a DNA region is across species, the greater an impact any variations therein are likely to have. A range of in silico analysis tools can also be used for the predication of a pathogenic effect (e.g. Align GVGD, Sorting Intolerant From Tolerant [SIFT], Polyphen, and Alamut) or the prediction of splice sites. One of the best means of determining pathogenicity, however, is the use of suitable functional assays and transgenic animal models [34,35].

From mutation to disease. A DNA mutation can cause qualitative or quantitative changes at the protein level, leading to either a dysfunctional/non-functional protein product and/or aberrant protein expression levels. Both mechanisms can in turn lead to CVD.

Once a mutation has been directly associated with a pathological phenotype a number of additional parameters need to be evaluated in order to maximize its value in the clinical setting. These parameters relate to the mode of inheritance of a mutation, which impacts directly the chances of detecting it in other family members of the patient, or his/her offspring. The categorization gonosomal or autosomal depends on whether the mutations are located on either of the sex chromosomes or not. For example a mutation on the Y chromosome will only affect males. The dominant or recessive nature relates to the need of one or both alleles, respectively, to carry the mutation for the pathogenic phenotype to develop. In hypertrophic cardiomyopathy (HCM) a number of cases have been reported with homozygosity for the pathogenic mutation. Nishi et al. first reported homozygosity for a MYH7 mutation in two brothers with HCM [36]. Homozygous mutations were also detected in MyBPC in HCM patients [37]. The patients who harbour homozygous mutations present with a more severe clinical phenotype than their heterozygous family members. These observations support the notion of a mutation dosage effect, in which a larger amount of the defective protein leads to a greater disruption of the sarcomere function and results in a more severe clinical outcome. For example, in our Egyptian HCM cohort, none of the mutation-positive patients were homozygous for the mutation detected (data not published) which might be explained either by the rarity of its occurrence in the specific cohort or due to technical limitations in the mutation screening method ().

Mutation screening by denaturing high performance liquid chromatography (dHPLC) using WAVE, Transgenomics. dHPLC can be used as an initial mutation screening method, being dependent on heteroduplex (wild type-mutant) formation, and variant profiles from the wild pattern are subsequently sequenced. Note however, that dHPLC is not capable of detecting homozygosity.

Importantly, a number of exceptions apply to the aforementioned inheritance mode rules, such as in the case of incomplete penetrance (a percentage of the individuals carrying the mutation fail to present the corresponding trait) where mutation carriers may not present with any symptoms even in the presence of a dominant mutation. Furthermore, the phenomena of variable expressivity (variations in a phenotype among individuals carrying a particular genotype) and epistasis (one gene is modified by one or several other genes, e.g. modifier genes) can lead to a range of pathological characteristics despite the presence of the same mutation. These parameters, potentially in combination with environmental factors, can often lead to significant clinical heterogeneity in most inherited CVDs, between unrelated individuals as well as family members carrying the same mutation () [38].

Role of genetic and environmental factors in determining the spectrum of the disease phenotype.(Strachan T, Read AP. Genes in pedigrees and populations in Human molecular genetics 3. 3rd ed. London; New York: Garland Press; 2004).

Another exception is this of compound heterozygotes (carriers of two different mutations on the two alleles of the same gene) or double heterozygotes (carriers of mutations in two different genes), which carry one copy of each mutation, yet they can develop the disease. Notably, the concomitant presence of multiple genetic defects contributing to the same disease is usually associated with a more severe clinical phenotype. For example, in HCM the presence of multiple pathogenic mutations could be included amongst the risk stratification criteria [39]. Multiple mutations have been observed in about 5% of HCM patients and they are usually associated with higher septal thickness and worse clinical outcomes, such as heart failure and sudden death [4043]. Double heterozygosity is commonly detected in the Myosin heavy chain (MYH7) and Myosin binding protein C (MyBPC) genes, probably because they represent the most commonly involved genes in the pathogenesis of HCM. Compound heterozygosity in MyBPC however, leading to the absence of a normal protein, has been reported to results in neonatal death in two independent cases, where the parents were each heterozygous for one of the mutations [44]. Similarly to HCM, double heterozygosity has been reported in other CVDs such as long QT, with a similar frequency of 5% [45].

Hereditary CVDs include a variety of different aspects and structures of the cardiovascular system such as inherited cardiomyopathies, arrhythmias, metabolic disorders affecting the heart, congenital heart diseases, as well as vascular disorders such as Marfan syndrome [4648]. Over the past two decades significant progress has been made towards the identification of the genetic basis of CVD, with tens of genes now known to be implicated in almost all of the different disorders. The magnitude of the role of genetics however, remains elusive. Although in some cases the pathogenesis appears to involve complex mechanisms and multifactorial (genetic and environmental) aetiology, multigenic inheritance (e.g. familial hypercholesterolemia: LDLR, APOB, ABCG5, ABCG8, ARH, PCSK9; hypertrophic cardiomyopathy: MYH7, TNNT2, TPM1, TNNI3, MYL2, MYBPC3, ACTC, MYL3) or even monogenic, also known as Mendelian, inheritance (e.g. Marfan syndrome: FNB1) has been described. Pinpointing the gene(s) and their specific mutations that lead to each pathological phenotype can give rise to valuable, complementary genetic diagnostic/prognostic tools for significantly improved clinical management of CVD patients and their families.

For example, the recently published consensus statement on the state of genetic testing for cardiomyopathies and channelopathies has elegantly presented the list of different genes which contribute by >5% to these inherited disorders. [49,50]. There are more than 50 distinct channelopathy/cardiomyopathy-associated genes with hundreds of mutations discovered to date. Each of these mutations/genes usually accounts for a small percentage of the reported cases, while in many cases the causative mutation/gene is never identified. For example, in channelopathies a mutation is found in <20% of short QT syndrome cases and up to 75% in long QT syndrome cases. An exceptional scenario is this of mutations in the cardiac ryanodine receptor (RYR2) gene in catecholaminergic polymorphic ventricular tachychardia, which account for up to 65% of affected patients [51]. In cardiomyopathies, positive genetic testing results range in frequency from <20% in restrictive cardiomyopathy to 60% in familial HCM. Despite the fact that two decades ago, HCM was termed a disease of the sarcomere involving at least 8 causative genes, the rate of mutation detection ranged in frequency from 2530% in MyBPC and MYH7 to 5% in TNNT2 and TNNTI3, and 1% in other sarcomeric genes [42,52]. Additionally, there are HCM phenocopies (same phenotype) associated with non-sarcomeric gene mutations and different modes of inheritance, which may on occasion be difficult to exclude from sarcomeric HCM based on clinical evaluation alone. Therefore, multiple genes need to be screened for a multigenic disease such as HCM.

Overall, our understanding of the genetic basis of CVD has been rapidly expanding over the years with important lessons learned both on monogenic as well as complex disease forms [53]. However, the true value of these findings lies in their translation to the clinical setting and their utilisation towards improved CVD diagnosis, prognosis and treatment. Along these lines, genetic testing is currently available for a number of CVDs in the form of clinical service in most Western countries, and increasingly in the developing world.

Genetic testing can serve three main goals in the clinical practice: first to determine the mode of inheritance of the specific disease in the specific family and identify if there is risk for other family members; second to organize the clinical assessment of unaffected family members through predictive genetic testing so as to distinguish those who are at risk for the disease and should have regular cardiac follow-up (mutation carriers) and those who are not (mutation non-carriers); third, following the establishment of distinct genotypephenotype correlations, the application of genetic testing in disease diagnosis, prognosis and personalized treatment (i.e. identification of the drugs to which each patient will respond best) [54].

The clinical value of genetic screening of a cardiovascular disease patient is therefore valuable initially at the diagnostic/prognostic/therapeutic level, provided the genotypephenotype associations have been established first. These associations vary considerably among different cardiovascular diseases, different genes and different mutations thereof. The relevance of genetic testing towards these three levels of clinical management is possibly best shown in the setting of the long QT syndrome [49,50]. It is critical to note however, that genetic testing in the cardiovascular disease setting cannot be the basis for clinical management of patients, but can serve a complementary role to the comprehensive clinical evaluation to better address the patient's and his/her family's needs.

Identifying the causative mutation of a proband further allows the genetic screening of its family members, a process of marked predictive power and therefore high importance in the cardiovascular clinic [55]. The significance of such pre-symptomatic genetic testing for the probands family members ranges from ensuring that unaffected mutation carriers receive regular clinical follow-up and prophylactic treatment (where available) to reassurance that clinically suspicious findings are unlikely to be indicative of the specific form of the disease in the absence of the specific family mutation (e.g. ) [56,57]. Importantly however, a negative genetic test result in the proband's family members cannot by itself exclude the presence of disease in general, since a large number of different genes and a variety of mutations thereof can contribute to the same or a different pathological cardiovascular phenotype and by chance, a family member could be a carrier of a different gene mutation.

Pedigree of an HCM positive family from the BA HCM Study. A pathogenic mutation in MYH7 exon 23 (Glu927Lys) was detected in the proband II-4. Echo screening of all siblings was undertaken, and sister II-10 was found to have an interventricular septal measurement of 14 mm. Genetic screening of all family members excluded HCM diagnosis for the sister (II-10).However, the symptom free and echo clear son of the proband, was positive for the mutation and therefore given a pre-symptomatic diagnosis of HCM at the age of12 years. Symbols in white represent unaffected individuals, in black are individuals with HCM based on clinical or genetic findings, and in blue are individuals who have not been screened by echo or genetic testing (unpublished data).

Genetic testing of children in the family has always posed an ethical concern, particularly for adult-onset diseases. Therefore pre-symptomatic testing of children should be extensively discussed with the family after a mutation has been identified in the proband, and in the context of the specific cardiovascular disease [58]. In cases where pre-symptomatic genetic screening and mutation identification has direct implications on the child's clinical follow-up, lifestyle adaptations and preventive treatments, it would be valuable to proceed with genetic testing, upon the parents approval. For example, for long QT syndrome and catecholaminergic polymorphic ventricular tachychardia, and occasionally in high risk HCM families, in which preventive measures or prophylactic therapy is advisable for asymptomatic mutation positive family members, genetic testing should be undertaken in early childhood, i.e. regardless of age. On the other hand, for late-onset and/or reduced penetrance diseases, it is reasonable to proceed with clinical monitoring as needed during childhood, leaving the genetic testing option open for when the individual reaches adulthood [49,50]. When a child has already presented with a CVD, the use of genetic testing is complementary to all other clinical tests, and especially valuable for identifying other family members at risk, since childhood-onset cases, even when presumed as sporadic, can often have a genetic aetiology. For example, approximately half of the presumed sporadic cases of childhood-onset hypertrophy have genetic causes [59].

Although the translation of molecular genetics to routine clinical practice is slow, a series of certified genetic testing centers (www.genetests.org) have been established, and guidelines have already been issued for a number of cardiovascular diseases such as HCM, dilated cardiomyopathy (DCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC) [60,61]. The consensus is that a minimum of three to four generation family history needs to be obtained, the relatives at risk need to be identified and directed for clinical screening, the potential genetic nature of the disease needs to be explained, and the possibility of genetic testing should be discussed where appropriate.

In order to follow these guidelines, cardiology clinics around the world need to ensure that cardiologists are provided with appropriate training in key genetic concepts, along with information on the latest developments in cardiovascular genetics and the best means to apply them in the clinic. Importantly, the close interaction between cardiologists, geneticists and genetic counsellors, especially in complex cases, will significantly expedite the benchside-to-bedside translation of the latest genetic discoveries and optimize the clinical care provided to the patient [62,63]. For example, when routine cardiovascular genetic screening fails to detect the causative mutations, screening can be extended to include broad gene panels and/or application of high throughput technologies. Similarly, in cases where new mutations are identified, targeted genetic tests can be designed, if needed, for screening family members at risk. Currently, different modes of cardiologist-geneticist interactions are being adopted in clinical settings around the world, a process that requires time, continuing education and to some extent, reorganization of health systems [64]. An example of such an evolving system of interdisciplinary interactions is that of the Egyptian National Genetic study of HCM ().

Combined clinical and genetic evaluation of CVD patients will allow for improved disease management and patient care.

In conclusion, cardiovascular genetic testing is valuable for improving the standards of care for CVD patients and their families at the diagnostic, prognostic and therapeutic level. Importantly, for healthcare systems worldwide, it further represents a cost-effective approach by enabling the timely identification of individuals at risk, ensuring regular follow-up only for the individuals at risk and early disease detection, as well as enabling, where possible, the use of disease preventative measures in order to minimize the environmental contributing factors [65]. To this end, clinical cardiovascular genetics is increasingly emphasized in undergraduate and postgraduate medical education and incorporated in cardiological clinics worldwide [54].

The tremendous technological advancements over the past decade have empowered the discovery of new biological concepts and the emergence of entirely new scientific fields. Among them, cardiac systems genetics a systems-based analysis of genetic variants considering all different levels spanning from their effect on the cardiac transcriptome, proteome, metabolome to organ physiology/pathophysiology (phenome) (). The global analysis of the downstream functional molecular and cellular implications of different genetic variants, will allow the meaningful integration of molecular and clinical data in a powerful way.

To fully unravel the intricate pathways regulating cardiac physiology and pathophysiology the global studies of the human genome will need to be extended to similar studies at the epigenome (chemical changes to the DNA and histone affecting the chromatin structure and function of the genome),transcriptome (the full set of transcripts produced from the human DNA), miRNome (the full set of microRNAs produced from the human DNA), proteome (the full set of proteins) and metabolome (full set of metabolites) levels.

Systems genetics will in turn, serve as an integral part of network medicine, an advanced form of molecular medicine, where perturbations, rather than individual molecules, are investigated as the underlying causes of complex diseases [66]. In cardiology, examples of important first steps in this direction are the identification of cardiac gene expression signatures related with response to left ventricular assist device implantation [67,68] and peripheral leukocyte expression signatures indicative of post-cardiac transplantation tissue rejection [69]. Parameters such as epigenetics and microRNAs are increasingly integrated in network medicine, adding new dimensions to the intricate mechanisms of cardiovascular disease (e.g. [70,71]). A likely next addition to network medicine, based on emerging new data [72,73], could be this of metagenomics the genomic investigation of micro-organisms inside the human body, and their effect on the global networks orchestrating human cardiac physiology/pathophysiology.

Cardiology is rapidly transformed with powerful new technologies expediting the acquisition of new knowledge and exciting new discoveries enriching our understanding of the intricate genotypephenotype correlations. The close interaction of cardiologists and geneticists is facilitating the transition of novel findings to clinical practice and vice versa. It is also enabling the rapid establishment of appropriate research strategies to address emerging clinical questions. Ultimately the convergence of the two disciplines promises to transform the way we perceive, manage and treat CVD.

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Molecular genetics made simple - PMC - National Center for ...

Figure 1: Dolly the sheep was the first cloned mammal.

The three letters DNA have now become associated with crime solving, paternity testing, human identification, and genetic testing. DNA can be retrieved from hair, blood, or saliva. With the exception of identical twins, each persons DNA is unique and it is possible to detect differences between human beings on the basis of their unique DNA sequence.

DNA analysis has many practical applications beyond forensics and paternity testing. DNA testing is used for tracing genealogy and identifying pathogens. In the medical field, DNA is used in diagnostics, new vaccine development, and cancer therapy. It is now possible to determine predisposition to many diseases by analyzing genes.

DNA is the genetic material passed from parent to offspring for all life on Earth. The technology of molecular genetics developed in the last half century has enabled us to see deep into the history of life to deduce the relationships between living things in ways never thought possible. It also allows us to understand the workings of evolution in populations of organisms. Over a thousand species have had their entire genome sequenced, and there have been thousands of individual human genome sequences completed. These sequences will allow us to understand human disease and the relationship of humans to the rest of the tree of life. Finally, molecular genetics techniques have revolutionized plant and animal breeding for human agricultural needs. All of these advances in biotechnology depended on basic research leading to the discovery of the structure of DNA in 1953, and the research since then has uncovered the details of DNA replication and the complex process leading to the expression of DNA in the form of proteins in the cell.

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4 Introduction to Molecular Genetics - University of Minnesota Twin Cities

DefinitionnounA branch of genetics that deal with the structure and function of genes at a molecular levelSupplementGenetics is a basically a study in heredity, particularly the mechanisms of hereditary transmission, and the variation of inherited characteristics among similar or related organisms. Some of the branches of genetics include behavioural genetics, classical genetics, cytogenetics, molecular genetics, developmental genetics, and population genetics.Molecular genetics, in particular, is a study of heredity and variation at the molecular level. It is focused on the flow and regulation of genetic information between DNA, RNA, and proteins. Its sub-fields are genomics (i.e. the study of all the nucleotide sequences, including structural genes, regulatory sequences, and noncoding DNA segments, in the chromosomes of an organism) and proteomics (i.e. the study of proteins from DNA replication). The different techniques employed in molecular genetics include amplification, polymerase chain reaction, DNA cloning, DNA isolation, mRNA isolation, and so on. Molecular genetics is essential in understanding and treating genetic disorders. It is regarded as the most advanced field of genetics. The Human Genome Project was a large scientific research endeavor in molecular genetics. It began in 1990s and finished in 2003 with the intent of identifying the genes and the sequences of chemical base pairs in human DNA.See also:

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Molecular genetics - Definition and Examples - Biology Online

Genetics has become one of the most diverse branches of science as it deals with heredity, inheritance, and how certain traits are expressed.

Molecular genetics focuses more on the molecules at work in geneticsspecifically DNA, RNA, and the proteins responsible for expressing traits.

This branch of genetics is instrumental in diagnosing genetic disorders. With molecular genetics, scientists and doctors can pinpoint abnormalities or changes within gene sequences.

The study of human DNA has propelled modern medicine towards actionable solutions for even the most difficult genetic conditions and mutations. By observing the molecular structure of DNA, geneticists can determine any deviation and mutation that may cause trouble down the road.

Molecular genetics is concerned with what makes DNAthat is, the molecules that are at work.1 Its a biomedical science concerned with human genes and the genetic material DNA consists of, as well as their nucleotide sequences and structures at the molecular level.

It is also considered the marriage of genetics and molecular biology, the study of the building blocks of every object.

This science shows us how genes inside our DNA determine everything from eye color to disease risk.

Geneticists, scientists, and medical professionals can determine how genes work and how any divergence from the norm can contribute to genetic disorders and abnormalities by exploring the special processes and properties of DNA molecules and their molecular mechanisms.

Molecular genetics breaks down into smaller fields, including:

Don't miss out on the opportunity to learn more about yourself. Read our best DNA test page to find the best one for you.

Yes. Molecular genetics falls under genetics.

Genetics is a broader branch of biology that deals with anything related to genes, traits, and inheritance. Its the study of how genes are passed down from parents to offspring through DNA sequences.2

19th-century monk Gregor Mendels famed pea plant experiments laid the foundation for modern genetics. Since then, niche branches of genetics have become specializations, such as:

DNA, or deoxyribonucleic acid, has a double helix structure thats made up of chemical components called nucleotides.3

Nucleotides, which form the DNA ladder, have three important parts:

The entirety of an organisms set of DNA or genetic material is called a genome. Each genome has all the instructions necessary for an organism to develop.

Every cell in that organism will have the same genome so that when they replicate themselves, they all still contain the exact same instructions.

Molecular genetic testing is when a DNA segment or a gene sequence is inspected for any mutations.4 A DNA strand is often looked closely at and analyzed to determine any variations at the molecular level.

Its compared to normal genetic material and any deviations or mutations are taken note of. Any variance in a gene is then explored.

Different mutations can lead to different genetic conditions. For example, a copy of a chromosome can lead to specific genetic disorders, depending on which chromosome has been duplicated.

Other conditions can also arise from the complex interplay of multiple genetic variants. So a thorough study of the DNA sequence is necessary to determine potential congenital risks.

A DNA molecule can also be further looked at to see how its structure contributes to the persons traits.

Genetic tests can be a little pricey, but its well worth the price tag when you consider what they can tell you.

Molecular genetics is being used today all over the world. Its especially used in a lot of genetic research and genetic testing.

When you get a genetic test done to find out more about your ancestry and heritage, you are investing in molecular genetics.

Your DNA sequence may exhibit similarities with the sequences of people who originate from a certain region. If you share certain key similarities, its a good indicator that you or your ancestors may also be from that area.

This helps you unlock more of your past and potentially provide you with closure around your past. Who knows, you may even find out you have royal ancestry.

If your parents had a genetic test done on you when they were pregnant with you to determine if you were at risk for any genetic disease, molecular genetics provided the results.

Geneticists and genetic counselors who tap into family history and rely on testing delve into your molecular structure and practice molecular genetics to give you better insight into your health. Many human diseases can be traced in family medical history via molecular genetics.

You can also determine if any diseases run in your family and what you can do to prevent contracting them.

In biological sciences, molecular genetics helps us understand the molecular basis of living things. It reveals the why behind how our bodies work at the very smallest level.

The biology of genes has helped us understand why certain genes are expressed over others, how we inherit traits, and the way our alleles work together.

Through the biological lens of genetics, weve been able to develop more medicine, apply more agricultural uses, and even explore gene editing.

Molecular genetics has made strides in forensics, given that its allowed us to identify DNA matches via fingerprints or other potential DNA samples.

Its also a huge help in the courtroom, as legal systems often use DNA testing to prove paternity or exonerate crimes.

Looking for a DNA test that's accurate and can tell you about your health and heritage?

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A Detailed Look at the Science of Molecular Genetics - KnowYourDNA

Research Interests

Mendelian principles have been the cornerstone for identifying nuclear genes in biological and diseases processes and ordering these genes into functional cascades. However, the limitation of Mendelian genetics to explain many complex traits has redirected attention beyond the nucleus. In addition to the nuclear genome, each eukaryotic cell contains hundreds to thousands of copies of mitochondrial genome, the small circular DNAs inside mitochondria. Mutations on mitochondrial genome often impair cellular energy homeostasis and have been linked to many diseases including various age-related disorders. Despite the immense impact of mtDNA mutations on health and disease, our understanding of mitochondrial genetics remains rudimentary. Genetic analyses on mitochondrial genome are complicated by the peculiarities of the mitochondrial genetic system that features maternal inheritance, polyploidy, and amitotic segregation.

We are working with fruit flies and other model organisms to understand the basic principles guiding the transmission of mitochondrial genome. We are trying to understand why evolution favors the transmission of mitochondrial genome from the maternal linage exclusively, how mothers limit the transmission of harmful mtDNA variants to their offsring, how organisms prevent the accumulation of mtDNA mutations in somatic tissues and with aging. We are also exploring the coordination and potential genetic conflicts between nuclear and mitochondrial genome, and their impact on health and diseases. Additionally, we are actively developing new tools to advance the genetic study of mtDNA.

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Molecular Genetics | NHLBI, NIH

Students seeking admission to the Genetics, Molecular and Cell Biology (GMCB) program apply to the Graduate School of Biomedical Sciences and select the GMCB program. Students interested in the Mammalian Genetics at JAX track must select this track when they apply to GMCB.

Prospective applicants are evaluated based on prior grades, three letters of recommendation, and personal statements. Prior research experience is strongly valued but is not required.

A personal interview is an important part of our evaluation process and may be conducted in person or virtually. An undergraduate major in the biological or life sciences is recommended, but not required.

The GRE is not required but can be submitted with the application.

The application is completed online on the GSBS Application Portal.

Information about application deadlines and the application process can be found in the Admissions section of this website.

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Genetics, Molecular & Cellular Biology Admissions

Branch of biology that studies biological systems at the molecular level

Molecular biology is a branch of biology that seeks to understand the molecular basis of biological activity in and between cells, including biomolecular synthesis, modification, mechanisms, and interactions.[1][2][3]

Though cells and other microscopic structures had been observed in living organisms as early as the 18th century, a detailed understanding of the mechanisms and interactions governing their behavior did not emerge until the 20th century, when technologies used in physics and chemistry had advanced sufficiently to permit their application in the biological sciences. The term 'molecular biology' was first used in 1945 by the English physicist William Astbury, who described it as an approach focused on discerning the underpinnings of biological phenomenai.e. uncovering the physical and chemical structures and properties of biological molecules, as well as their interactions with other molecules and how these interactions explain observations of so-called classical biology, which instead studies biological processes at larger scales and higher levels of organization.[4] In 1953, Francis Crick, James Watson, Rosalind Franklin, and their colleagues at the Medical Research Council Unit, Cavendish Laboratory, were the first to describe the double helix model for the chemical structure of deoxyribonucleic acid (DNA), which is often considered a landmark event for the nascent field because it provided a physico-chemical basis by which to understand the previously nebulous idea of nucleic acids as the primary substance of biological inheritance. They proposed this structure based on previous research done by Franklin, which was conveyed to them by Maurice Wilkins and Max Perutz.[5] Their work led to the discovery of DNA in other microorganisms, plants, and animals.[6]

The field of molecular biology includes techniques which enable scientists to learn about molecular processes.[7] These techniques are used to efficiently target new drugs, diagnose disease, and better understand cell physiology.[8] Some clinical research and medical therapies arising from molecular biology are covered under gene therapy, whereas the use of molecular biology or molecular cell biology in medicine is now referred to as molecular medicine.

Molecular biology sits at the intersection of biochemistry and genetics; as these scientific disciplines emerged and evolved in the 20th century, it became clear that they both sought to determine the molecular mechanisms which underlie vital cellular functions.[9][10] Advances in molecular biology have been closely related to the development of new technologies and their optimization.[11] Molecular biology has been elucidated by the work of many scientists, and thus the history of the field depends on an understanding of these scientists and their experiments.[citation needed]

The field of genetics arose from attempts to understand the set of rules underlying reproduction and heredity, and the nature of the hypothetical units of heredity known as genes. Gregor Mendel pioneered this work in 1866, when he first described the laws of inheritance he observed in his studies of mating crosses in pea plants.[12] One such law of genetic inheritance is the law of segregation, which states that diploid individuals with two alleles for a particular gene will pass one of these alleles to their offspring.[13] Because of his critical work, the study of genetic inheritance is commonly referred to as Mendelian genetics.[14]

A major milestone in molecular biology was the discovery of the structure of DNA. This work began in 1869 by Friedrich Miescher, a Swiss biochemist who first proposed a structure called nuclein, which we now know to be (deoxyribonucleic acid), or DNA.[15] He discovered this unique substance by studying the components of pus-filled bandages, and noting the unique properties of the "phosphorus-containing substances".[16] Another notable contributor to the DNA model was Phoebus Levene, who proposed the "polynucleotide model" of DNA in 1919 as a result of his biochemical experiments on yeast.[17] In 1950, Erwin Chargaff expanded on the work of Levene and elucidated a few critical properties of nucleic acids: first, the sequence of nucleic acids varies across species.[18] Second, the total concentration of purines (adenine and guanine) is always equal to the total concentration of pyrimidines (cysteine and thymine).[15] This is now known as Chargaff's rule. In 1953, James Watson and Francis Crick published the double helical structure of DNA,[19] based on the X-ray crystallography work done by Rosalind Franklin which was conveyed to them by Maurice Wilkins and Max Perutz.[5] Watson and Crick described the structure of DNA and conjectured about the implications of this unique structure for possible mechanisms of DNA replication.[19] Watson and Crick were awarded the Nobel Prize in Physiology or Medicine in 1962, along with Wilkins, for proposing a model of the structure of DNA.[6]

In 1961, it was demonstrated that when a gene encodes a protein, three sequential bases of a gene's DNA specify each successive amino acid of the protein.[20] Thus the genetic code is a triplet code, where each triplet (called a codon) specifies a particular amino acid. Furthermore, it was shown that the codons do not overlap with each other in the DNA sequence encoding a protein, and that each sequence is read from a fixed starting point.During 19621964, through the use of conditional lethal mutants of a bacterial virus,[21] fundamental advances were made in our understanding of the functions and interactions of the proteins employed in the machinery of DNA replication, DNA repair, DNA recombination, and in the assembly of molecular structures.[22]

In 1928, Frederick Griffith, encountered a virulence property in pneumococcus bacteria, which was killing lab rats. According to Mendel, prevalent at that time, gene transfer could occur only from parent to daughter cells. Griffith advanced another theory, stating that gene transfer occurring in member of same generation is known as horizontal gene transfer (HGT). This phenomenon is now referred to as genetic transformation.[23]

Griffith's experiment addressed the pneumococcus bacteria, which had two different strains, one virulent and smooth and one avirulent and rough. The smooth strain had glistering appearance owing to the presence of a type of specific polysaccharide a polymer of glucose and glucuronic acid capsule. Due to this polysaccharide layer of bacteria, a host's immune system cannot recognize the bacteria and it kills the host. The other, avirulent, rough strain lacks this polysaccharide capsule and has a dull, rough appearance.[citation needed]

Presence or absence of capsule in the strain, is known to be genetically determined. Smooth and rough strains occur in several different type such as S-I, S-II, S-III, etc. and R-I, R-II, R-III, etc. respectively. All this subtypes of S and R bacteria differ with each other in antigen type they produce.[6]

The AveryMacLeodMcCarty experiment was a landmark study conducted in 1944 that demonstrated that DNA, not protein as previously thought, carries genetic information in bacteria. Oswald Avery, Colin Munro MacLeod, and Maclyn McCarty used an extract from a strain of pneumococcus that could cause pneumonia in mice. They showed that genetic transformation in the bacteria could be accomplished by injecting them with purified DNA from the extract. They discovered that when they digested the DNA in the extract with DNase, transformation of harmless bacteria into virulent ones was lost. This provided strong evidence that DNA was the genetic material, challenging the prevailing belief that proteins were responsible. It laid the basis for the subsequent discovery of its structure by Watson and Crick.

Confirmation that DNA is the genetic material which is cause of infection came from the HersheyChase experiment. They used E.coli and bacteriophage for the experiment. This experiment is also known as blender experiment, as kitchen blender was used as a major piece of apparatus. Alfred Hershey and Martha Chase demonstrated that the DNA injected by a phage particle into a bacterium contains all information required to synthesize progeny phage particles. They used radioactivity to tag the bacteriophage's protein coat with radioactive sulphur and DNA with radioactive phosphorus, into two different test tubes respectively. After mixing bacteriophage and E.coli into the test tube, the incubation period starts in which phage transforms the genetic material in the E.coli cells. Then the mixture is blended or agitated, which separates the phage from E.coli cells. The whole mixture is centrifuged and the pellet which contains E.coli cells was checked and the supernatant was discarded. The E.coli cells showed radioactive phosphorus, which indicated that the transformed material was DNA not the protein coat.

The transformed DNA gets attached to the DNA of E.coli and radioactivity is only seen onto the bacteriophage's DNA. This mutated DNA can be passed to the next generation and the theory of Transduction came into existence. Transduction is a process in which the bacterial DNA carry the fragment of bacteriophages and pass it on the next generation. This is also a type of horizontal gene transfer.[6]

The Meselson-Stahl experiment was a landmark experiment in molecular biology that provided evidence for the semiconservative replication of DNA. Conducted in 1958 by Matthew Meselson and Franklin Stahl, the experiment involved growing E. coli bacteria in a medium containing heavy isotope of nitrogen (15N) for several generations. This caused all the newly synthesized bacterial DNA to be incorporated with the heavy isotope.

After allowing the bacteria to replicate in a medium containing normal nitrogen (14N), samples were taken at various time points. These samples were then subjected to centrifugation in a density gradient, which separated the DNA molecules based on their density.

The results showed that after one generation of replication in the 14N medium, the DNA formed a band of intermediate density between that of pure 15N DNA and pure 14N DNA. This supported the semiconservative DNA replication proposed by Watson and Crick, where each strand of the parental DNA molecule serves as a template for the synthesis of a new complementary strand, resulting in two daughter DNA molecules, each consisting of one parental and one newly synthesized strand.

The Meselson-Stahl experiment provided compelling evidence for the semiconservative replication of DNA, which is fundamental to the understanding of genetics and molecular biology.

In the early 2020s, molecular biology entered a golden age defined by both vertical and horizontal technical development. Vertically, novel technologies are allowing for real-time monitoring of biological processes at the atomic level.[24] Molecular biologists today have access to increasingly affordable sequencing data at increasingly higher depths, facilitating the development of novel genetic manipulation methods in new non-model organisms. Likewise, synthetic molecular biologists will drive the industrial production of small and macro molecules through the introduction of exogenous metabolic pathways in various prokaryotic and eukaryotic cell lines.[25]

Horizontally, sequencing data is becoming more affordable and used in many different scientific fields. This will drive the development of industries in developing nations and increase accessibility to individual researchers. Likewise, CRISPR-Cas9 gene editing experiments can now be conceived and implemented by individuals for under $10,000 in novel organisms, which will drive the development of industrial and medical applications.[26]

The following list describes a viewpoint on the interdisciplinary relationships between molecular biology and other related fields.[27]

While researchers practice techniques specific to molecular biology, it is common to combine these with methods from genetics and biochemistry. Much of molecular biology is quantitative, and recently a significant amount of work has been done using computer science techniques such as bioinformatics and computational biology. Molecular genetics, the study of gene structure and function, has been among the most prominent sub-fields of molecular biology since the early 2000s. Other branches of biology are informed by molecular biology, by either directly studying the interactions of molecules in their own right such as in cell biology and developmental biology, or indirectly, where molecular techniques are used to infer historical attributes of populations or species, as in fields in evolutionary biology such as population genetics and phylogenetics. There is also a long tradition of studying biomolecules "from the ground up", or molecularly, in biophysics.[30]

Molecular cloning is used to isolate and then transfer a DNA sequence of interest into a plasmid vector.[31] This recombinant DNA technology was first developed in the 1960s.[32] In this technique, a DNA sequence coding for a protein of interest is cloned using polymerase chain reaction (PCR), and/or restriction enzymes, into a plasmid (expression vector). The plasmid vector usually has at least 3 distinctive features: an origin of replication, a multiple cloning site (MCS), and a selective marker (usually antibiotic resistance). Additionally, upstream of the MCS are the promoter regions and the transcription start site, which regulate the expression of cloned gene.

This plasmid can be inserted into either bacterial or animal cells. Introducing DNA into bacterial cells can be done by transformation via uptake of naked DNA, conjugation via cell-cell contact or by transduction via viral vector. Introducing DNA into eukaryotic cells, such as animal cells, by physical or chemical means is called transfection. Several different transfection techniques are available, such as calcium phosphate transfection, electroporation, microinjection and liposome transfection. The plasmid may be integrated into the genome, resulting in a stable transfection, or may remain independent of the genome and expressed temporarily, called a transient transfection.[33][34]

DNA coding for a protein of interest is now inside a cell, and the protein can now be expressed. A variety of systems, such as inducible promoters and specific cell-signaling factors, are available to help express the protein of interest at high levels. Large quantities of a protein can then be extracted from the bacterial or eukaryotic cell. The protein can be tested for enzymatic activity under a variety of situations, the protein may be crystallized so its tertiary structure can be studied, or, in the pharmaceutical industry, the activity of new drugs against the protein can be studied.[35]

Polymerase chain reaction (PCR) is an extremely versatile technique for copying DNA. In brief, PCR allows a specific DNA sequence to be copied or modified in predetermined ways. The reaction is extremely powerful and under perfect conditions could amplify one DNA molecule to become 1.07 billion molecules in less than two hours. PCR has many applications, including the study of gene expression, the detection of pathogenic microorganisms, the detection of genetic mutations, and the introduction of mutations to DNA.[36] The PCR technique can be used to introduce restriction enzyme sites to ends of DNA molecules, or to mutate particular bases of DNA, the latter is a method referred to as site-directed mutagenesis. PCR can also be used to determine whether a particular DNA fragment is found in a cDNA library. PCR has many variations, like reverse transcription PCR (RT-PCR) for amplification of RNA, and, more recently, quantitative PCR which allow for quantitative measurement of DNA or RNA molecules.[37][38]

Gel electrophoresis is a technique which separates molecules by their size using an agarose or polyacrylamide gel.[39] This technique is one of the principal tools of molecular biology. The basic principle is that DNA fragments can be separated by applying an electric current across the gel - because the DNA backbone contains negatively charged phosphate groups, the DNA will migrate through the agarose gel towards the positive end of the current.[39] Proteins can also be separated on the basis of size using an SDS-PAGE gel, or on the basis of size and their electric charge by using what is known as a 2D gel electrophoresis.[40]

The Bradford assay is a molecular biology technique which enables the fast, accurate quantitation of protein molecules utilizing the unique properties of a dye called Coomassie Brilliant Blue G-250.[41] Coomassie Blue undergoes a visible color shift from reddish-brown to bright blue upon binding to protein.[41] In its unstable, cationic state, Coomassie Blue has a background wavelength of 465nm and gives off a reddish-brown color.[42] When Coomassie Blue binds to protein in an acidic solution, the background wavelength shifts to 595nm and the dye gives off a bright blue color.[42] Proteins in the assay bind Coomassie blue in about 2 minutes, and the protein-dye complex is stable for about an hour, although it is recommended that absorbance readings are taken within 5 to 20 minutes of reaction initiation.[41] The concentration of protein in the Bradford assay can then be measured using a visible light spectrophotometer, and therefore does not require extensive equipment.[42]

This method was developed in 1975 by Marion M. Bradford, and has enabled significantly faster, more accurate protein quantitation compared to previous methods: the Lowry procedure and the biuret assay.[41] Unlike the previous methods, the Bradford assay is not susceptible to interference by several non-protein molecules, including ethanol, sodium chloride, and magnesium chloride.[41] However, it is susceptible to influence by strong alkaline buffering agents, such as sodium dodecyl sulfate (SDS).[41]

The terms northern, western and eastern blotting are derived from what initially was a molecular biology joke that played on the term Southern blotting, after the technique described by Edwin Southern for the hybridisation of blotted DNA. Patricia Thomas, developer of the RNA blot which then became known as the northern blot, actually did not use the term.[43]

Named after its inventor, biologist Edwin Southern, the Southern blot is a method for probing for the presence of a specific DNA sequence within a DNA sample. DNA samples before or after restriction enzyme (restriction endonuclease) digestion are separated by gel electrophoresis and then transferred to a membrane by blotting via capillary action. The membrane is then exposed to a labeled DNA probe that has a complement base sequence to the sequence on the DNA of interest.[44] Southern blotting is less commonly used in laboratory science due to the capacity of other techniques, such as PCR, to detect specific DNA sequences from DNA samples. These blots are still used for some applications, however, such as measuring transgene copy number in transgenic mice or in the engineering of gene knockout embryonic stem cell lines.[30]

The northern blot is used to study the presence of specific RNA molecules as relative comparison among a set of different samples of RNA. It is essentially a combination of denaturing RNA gel electrophoresis, and a blot. In this process RNA is separated based on size and is then transferred to a membrane that is then probed with a labeled complement of a sequence of interest. The results may be visualized through a variety of ways depending on the label used; however, most result in the revelation of bands representing the sizes of the RNA detected in sample. The intensity of these bands is related to the amount of the target RNA in the samples analyzed. The procedure is commonly used to study when and how much gene expression is occurring by measuring how much of that RNA is present in different samples, assuming that no post-transcriptional regulation occurs and that the levels of mRNA reflect proportional levels of the corresponding protein being produced. It is one of the most basic tools for determining at what time, and under what conditions, certain genes are expressed in living tissues.[45][46]

A western blot is a technique by which specific proteins can be detected from a mixture of proteins.[47] Western blots can be used to determine the size of isolated proteins, as well as to quantify their expression.[48] In western blotting, proteins are first separated by size, in a thin gel sandwiched between two glass plates in a technique known as SDS-PAGE. The proteins in the gel are then transferred to a polyvinylidene fluoride (PVDF), nitrocellulose, nylon, or other support membrane. This membrane can then be probed with solutions of antibodies. Antibodies that specifically bind to the protein of interest can then be visualized by a variety of techniques, including colored products, chemiluminescence, or autoradiography. Often, the antibodies are labeled with enzymes. When a chemiluminescent substrate is exposed to the enzyme it allows detection. Using western blotting techniques allows not only detection but also quantitative analysis. Analogous methods to western blotting can be used to directly stain specific proteins in live cells or tissue sections.[47][49]

The eastern blotting technique is used to detect post-translational modification of proteins. Proteins blotted on to the PVDF or nitrocellulose membrane are probed for modifications using specific substrates.[50]

A DNA microarray is a collection of spots attached to a solid support such as a microscope slide where each spot contains one or more single-stranded DNA oligonucleotide fragments. Arrays make it possible to put down large quantities of very small (100 micrometre diameter) spots on a single slide. Each spot has a DNA fragment molecule that is complementary to a single DNA sequence. A variation of this technique allows the gene expression of an organism at a particular stage in development to be qualified (expression profiling). In this technique the RNA in a tissue is isolated and converted to labeled complementary DNA (cDNA). This cDNA is then hybridized to the fragments on the array and visualization of the hybridization can be done. Since multiple arrays can be made with exactly the same position of fragments, they are particularly useful for comparing the gene expression of two different tissues, such as a healthy and cancerous tissue. Also, one can measure what genes are expressed and how that expression changes with time or with other factors.There are many different ways to fabricate microarrays; the most common are silicon chips, microscope slides with spots of ~100 micrometre diameter, custom arrays, and arrays with larger spots on porous membranes (macroarrays). There can be anywhere from 100 spots to more than 10,000 on a given array. Arrays can also be made with molecules other than DNA.[51][52][53][54]

Allele-specific oligonucleotide (ASO) is a technique that allows detection of single base mutations without the need for PCR or gel electrophoresis. Short (2025 nucleotides in length), labeled probes are exposed to the non-fragmented target DNA, hybridization occurs with high specificity due to the short length of the probes and even a single base change will hinder hybridization. The target DNA is then washed and the unhybridized probes are removed. The target DNA is then analyzed for the presence of the probe via radioactivity or fluorescence. In this experiment, as in most molecular biology techniques, a control must be used to ensure successful experimentation.[55][56]

In molecular biology, procedures and technologies are continually being developed and older technologies abandoned. For example, before the advent of DNA gel electrophoresis (agarose or polyacrylamide), the size of DNA molecules was typically determined by rate sedimentation in sucrose gradients, a slow and labor-intensive technique requiring expensive instrumentation; prior to sucrose gradients, viscometry was used. Aside from their historical interest, it is often worth knowing about older technology, as it is occasionally useful to solve another new problem for which the newer technique is inappropriate.[57]

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Molecular biology - Wikipedia

Researchers map 50,000 of DNAs mysterious knots in the human genome  EurekAlert

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Researchers map 50,000 of DNAs mysterious knots in the human genome - EurekAlert

Artificial selection of mutations in two nearby genes gave rise to shattering resistance in soybean  Nature.com

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Artificial selection of mutations in two nearby genes gave rise to shattering resistance in soybean - Nature.com

Mainz Biomed Expands Corporate Health Program for ColoAlert with the Addition of Three New Companies in Germany  Marketscreener.com

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Mainz Biomed Expands Corporate Health Program for ColoAlert with the Addition of Three New Companies in Germany - Marketscreener.com

Molecular Genetics and Metabolism contributes to the understanding of the metabolic and molecular basis of disease. This peer reviewed journal publishes articles describing investigations that use the tools of biochemical genetics and molecular genetics for studies of normal and disease states in humans and animal models.

In addition to original research articles, minireviews reporting timely advances and commentaries providing novel insights are considered.

Research Areas include:

- Newborn Screening and Diagnosis of Inherited Metabolic Diseases- Clinical Management and Treatment of Inborn Errors of Metabolism- Normal and Pathogenic Functioning Related to Biochemical Genetic Disease- Biochemical Studies of Primary and Secondary Enzyme Defects- Thresholds, Moonlighting Functions of Proteins and Biochemical Network Modules- Intercellular and Intracellular Metabolic Relationships

Authors are also welcome to submit to the journal?s open access companion title, Molecular Genetics and Metabolism Reports, which welcomes brief research articles, sequence reports, case reports and letters to the editors.

Molecular Genetics and Metabolism contributes to the understanding of the metabolic and molecular basis of disease. This peer reviewed journal publishes articles describing investigations that use the tools of biochemical genetics and molecular genetics for studies of normal and disease states in

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Molecular Genetics and Metabolism | Journal - ScienceDirect

People don't mate randomly but the flawed assumption that they do is an essential part of many studies linking genes to diseases and traits  The Conversation Indonesia

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People don't mate randomly but the flawed assumption that they do is an essential part of many studies linking genes to diseases and traits - The...

The Molecular & Cell Biology & Genetics (MCBG) program is an interdisciplinary graduate program recognizing the need for highly trained scientists conversant across various disciplines.

The program provides a broad education-training program for graduate students interested in biomedical problems that cross disciplinary boundaries and offers the opportunity for students to choose from approximately 70 faculty in 10 different departments/centers to pursue their research interests. This program offers both MS and PhD degrees and focuses on the study of the structure, function and makeup of biologically important molecules within the context of the living cells. Our curriculum and research activities are tailored to students needs and interests. See our areas of research interest.

Our faculty are at the forefront of new advances in the biomedical sciences and new developments in techniques for understanding the genetic and molecular basis of developmental pathways and disease states such as cancer, aging, AIDS, malaria and neurological disorders. Consequently, students can pursue a diverse variety of projects that range from the design and development of new therapeutic treatment strategies to the characterization of the molecular mechanisms that underlie various cellular processes and diseases. This intensive and research-oriented program provides students with opportunities to perform cutting edge biomedical research employing multidisciplinary strategies. Learn more about our faculty.

Learn more about the curriculum for the Molecular & Cell Biology & Genetics program.

Recent Molecular & Cell Biology & Genetics program graduates are at:

Academic or Clinical Institutions Children's Hospital of Philadelphia Columbia University Herbert Irving Comprehensive Cancer Center Dana-Farber Cancer Institute Duke University Drexel University College of Medicine Fox Chase Cancer Center Fred Hutchinson Cancer Research Center Institute for Protein Innovation Massachusetts General Hospital Cancer Center Rutgers University Thomas Jefferson University University of California Los Angeles, School of Medicine University of Minnesota University of Pennsylvania Center for Innovation University of Pennsylvania Perelman School of Medicine Vanderbilt University Medical Center

Academic Institutions (PhD Studies after MS completion) Drexel University College of Medicine Emory University Medical University of South Carolina Ohio State University Temple University Thomas Jefferson University University of Delaware University of Pennsylvania Perelman School of Medicine

Biotech and Pharmaceutical Companies Alcon Absorption Systems BioTek Instruments Biomeme Boehringer Ingelheim Carisma Therapeutics Castle Creek Biosciences CellOxess EMD Serono Eurofins Scientific Fishawack Group of Companies Genewiz GlaxoSmithKline Illumina Janssen Pharmaceutical Companies of Johnson & Johnson Merck & Co. Opentrons Labworks Pharmaceutical Product Development Quest Diagnostics Rockland Immunochemicals Sana Biotechnology Spark Therapeutics Tmunity Therapeutics Incorporated UCB

MCBG/Cancer Bio Graduate Programs Seminar Series Spring 2022

Learn more about the Spring 2022 Seminar Series.

Alyssa Sanders (Mentor: Mauricio Reginato, PhD): Outstanding Junior Graduate Student Poster, Honorable Mention

Daniel Kantner has started his PhD studies in the Biological Sciences PhD program at Temple University. Daniel conducted his MS research in the laboratory of Joris Beld, PhD, Department of Microbiology & Immunology.

Daniel Slusaw has started his PhD studies in the Biological Sciences PhD program at University of Delaware. Daniel conducted his MS research in the laboratory of Srinivas Somarowthu, PhD, Department of Biochemistry & Molecular Biology.

Emily Esquea has successfully transitioned into the MCBG PhD Program at Drexel University College of Medicine. Emily will be conducting her PhD research in the laboratory of Mauricio Reginato, PhD, Department of Biochemistry & Molecular Biology.

Nima Sarfaraz has successfully transitioned into the MCBG PhD Program at Drexel University College of Medicine. Nima will be conducting his PhD research in the laboratory of Michael Bouchard, PhD, Department of Biochemistry & Molecular Biology.

Mitchell Parker received the Ruth L. Kirschstein National Research Service Award (F30) from the National Institute of General Medical Sciences (NIH-NIGMS).Mentor: Roland Dunbrack, PhD, Fox Chase Cancer CenterProject title: "Creating a Unified RAS Structural Nomenclature to Compare the Impact of Oncogenic Mutations on KRAS, NRAS, and HRAS"

John Chojnowsky received the 2020 Dean's Fellowship for Excellence in ResearchMentor: Todd Strochlic, VMD, PhD, Department of Biochemistry & Molecular BiologyProject title: "Evaluating a novel mechanism of regulation for a master kinase"

Theodore Gurrola has successfully transitioned into the MCBG PhD Program at Drexel University College of Medicine. Ted will be conducting his PhD research in the laboratory of Brian Wigdahl, PhD, Department of Microbiology & Immunology.

See a complete listing of this year's Discovery Day winners.

Stephano Iglesias will start his PhD studies in the Biochemistry & Molecular Pharmacology PhD program at Thomas Jefferson University. Stephano has been conducting his MS research in the laboratory of Shae Padrick, PhD, Department of Biochemistry & Molecular Biology.

Manali Potnis has been serving as a student representative on the Women in Medicine and Science Committee (WIMSC). The mission of the committee is to support and promote the professional development, career advancement and leadership of women in medicine and science at Drexel University College of Medicine. WIMSC hosts seminars, networking events, and awards that focus on empowering women in science. The committee is currently headed by Dr. Karen Berkowitz. The multidisciplinary group includes scientists, physicians, technicians, and graduate student representatives. Members attend monthly meetings with agendas working toward increasing representation of women in science, a fair representation of women, and empowerment of minorities. Manalitransitioned from the MS to the PhD program in July 2019, and is a student in the laboratory of Christian Sell, PhD (Department of Pathology & Laboratory Medicine)

Jasmine Peake's presentation was selected as a top poster at the DNA Damage, Mutation, and Cancer Gordon Research Conference in 2020. She received the 2019 Outstanding Graduate Student Mentorship Award for her commitment to mentoring and supporting undergraduate and junior graduate students. She was also the College of Medicine finalist for the 2019 Drexel Common Good Award. Jasmine is a Southern Regional Education Board State doctoral fellow for the 2019 Institute on Teaching and Mentoring. Jasmine has been conducting her doctoral dissertation research in the laboratory of Eishi Noguchi, PhD (Department of Biochemistry & Molecular Biology).

Drexel graduate and medical students met Dr. James Allison, 2018 Nobel Laureate and 2019 Benjamin Franklin Medal winner. Pictured from left to right: Maggie O'Connor (MCBG MD/PhD Candidate); Samuel Flashner (MCBG PhD Candidate); Dr. James Allison; Dr. Brad Jameson (Professor, Department of Biochemistry & Molecular Biology); Mitchel Parker (MCBG MD/PhD Candidate); Jasmine Peake (MCBG PhD Candidate); and Joseph Assali (MD Candidate).

Drexel graduate and medical students met with 2018 Nobel Prize winner Dr. James Allison to discuss his work, following his seminar entitled "Immune Checkpoint Blockade in Cancer Therapy: New Insights, Opportunities and Prospects for Cures." Dr. Allison's lecture at Drexel University was held in conjunction with his receipt of the 2019 Benjamin Franklin Medal in Life Sciences. Dr. Allison received the Nobel Prize in Medicine for work on immune checkpoint blockade as a treatment for cancer. He is credited with devising an entirely new approach to cancer therapy and saving many lives.

See the rest here:
Molecular and Cell Biology and Genetics - Master of Science / PhD ...

Students and faculty gathered in Keller Auditorium for the first-ever poster presentation and awards ceremony to highlight the research achievements and accomplishments of students in the Skeletal Biology and Regeneration (SBR) Area of Concentration in the Biomedical Science Graduate Program at UConn Health.

Two highly prestigious awardsthe William B. Upholt Achievement Award and Eric N. James Scholar Award were announced at the ceremony after the student poster presentations.

Emma Wentworth Winchester presents her research during the poster session

Sandro D. Cloiseau presents his research during the poster session

Adam Tanguay presents his research during the poster session

Kaitlyn Flint presents her research during the poster session

Prachi Arpitbhai Thakore presents her research during the poster session

Students present their research during the poster session

Steven Toro presents his research during the poster session

Patricia Hare presents her research during the poster session

Dr. Marja Hurley and Kai Clarke during the student poster presentation

Stephanie Wong presents her research during the poster session.

Students present their research during the poster session

Dr. Laura Doherty accepts the 2021 William B. Upholt Achievement Award

Dr. Laura Doherty accepts the 2021 William B. Upholt Achievement Award

Dr. Marja Hurley and family of Dr. Eric N. James present the Eric N. James Scholar Award

Rosalie Bordett accepts the 2021 Eric N. James Scholar Award

SBR students, faculty, and family of Dr. Eric James and William B. Upholt gather for a group photo

The SBR program at UConn Health focuses on the cellular, molecular, and genetic processes related to skeletal development, diseases, injuries, and their regeneration. The program, which includes over 25 research labs, spans both the Schools of Dental Medicine and Medicine.

The multidisciplinary research and broad expertise within SBR is a strength of our program, said Dr. Rosa Guzzo, director of the SBR program, in her opening remarks. There is vast richness and diversity within SBR research.

Dr. Bruce Liang, dean of the UConn School of Medicine and interim CEO of UConn Health, in his remarks congratulating the students noted that the program is a true collaborative effort at UConn Health.

Dr. Caroline Dealy, associate professor in the Department of Craniofacial Sciences and the alumni and awards committee chair for the SBR program, introduced the William B. Upholt Achievement award and reflected fondly on Upholts research and leadership at UConn Health.

Scientifically, his work was always on the cutting edge, Dealy said. He was a leader in developing programs, establishing them, keeping them going, and being the glue holding them together.

Upholts wife, Mary Lee Morrison Upholt, was also in attendance.

The 2020 winner of the William B. Upholt Achievement Award, Dr. Elise Pitman, delivered virtual remarks from her postdoctoral program in Scotland. Pitman discussed her research including treating autoimmune colitis and colorectal cancer, as well as her avid role as a student advocate for students in research fields.

The 2021 winner, Dr. Laura Doherty, discussed her thesis in fracture healing using mass models, as well as her passion of supporting women in aviation.

The William B. Upholt Achievement Award was established to honor Upholts impact on research and graduate education, as well as his lifelong personal commitment to human rights, civic activism, and to the environment.

Dr. Lakshmi Nair, associate director of the SBR program, professor, Department of Orthopaedic Surgery and Connecticut Convergence Institute, and Dr. Marja Hurley, Board of Trustees Distinguished Professor of Medicine and Orthopedic surgery and associate dean of the Health Career Opportunity Programs at UConn Health, introduced the Eric N. James Scholar Award. Nair and Hurley both recounted Dr. Eric N. James time at UConn Health and his involvement mentoring young men of color.

Eric was humble, genuine, and committed to education, research, scholarship, and community service. He was always willing to assist others. I am truly pleased we are able to honor Dr. James in this manner, said Hurley.

James family was also in attendance for the award ceremony.

The winner of the 2021 Eric N. James Scholar Award, Rosalie Bordett, accepted the award and talked about her desire to help students discover their passion for science and make academia a more welcoming place for students. Bordett also discussed her experience serving as mentor for high school, undergraduate students and her desire to reach students in underrepresented backgrounds.

The Eric N. James Scholar Award honors James scientific achievements and reflects his deep commitment to helping others through teaching and mentorship. Consistent with James mission to promote education and training of diverse individuals, the Award emphasizes service to underrepresented groups, as well as scholarly and research achievement, especially by members of underrepresented groups.

The William B. Upholt and Eric N. James Scholar awards are made possible by donations from SBR alumni and faculty, private donors, and the School of Dental Medicine; additional support for this event was provided by the UConn Foundation and the Connecticut Convergence Institute.

Contribute to the William B. Upholt Student Achievement Award Fund.

Contribute to the Eric N. James Scholar Award Fund.

The full list of award winners is below:

2020 William B. Upholt Achievement Award

Elise PitmonPh.D. thesis mentor: Dr. Kepeng Wang, Department of Immunology

2021 William B. Upholt Achievement Award

Laura DohertyPh.D. thesis mentor: Dr. Archana Sanjay, Department of Orthopaedic Surgery

The 2021 William B. Upholt Achievement Award nominees

Patricia HarePh.D. thesis mentor: Dr. Wendy Mok, Department of Molecular Biology and Biophysics

Patrick McMullanPh.D. thesis mentor: Dr. Emily Germain-Lee, Department of Pediatrics

Adam TanguayPh.D. thesis mentor: Dr. Tannin Schmidt, Department of Biomedical Engineering

Stephanie WongPh.D. thesis mentor: Dr. Alix Deymier, Department of Biomedical Engineering

2021 Eric N. James Scholar Award

Rosalie BordettPh.D. thesis mentor: Dr. Sangamesh Kumbar, Departments of Orthopedic Surgery, Biomedical Engineering, and Materials Science

2021 runner-up of the 2021 Eric N. James Scholar Award

Britta PetersenPh.D. thesis mentor: Dr. Marc Hansen, Departments of Medicine, Genetics and Developmental Biology

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Skeletal Biology and Regeneration Students Recognized For Research Excellence - UConn Today - University of Connecticut