Genetics & Mechanisms of Inheritance 2023 PDF

Genetics and Mechanisms of Inheritance Brianna Hanson, PA-C Summer 2023 Basics of Genetic Inheritance Genotype vs phenotype Homozygous vs heterozygous Recessive traits vs dominant alleles Basics of genetics Two polynucleotide chains that coil into a double helix Each chain made of a sugarphosphate b...

Genetics and Mechanisms of Inheritance Brianna Hanson, PA-C Summer 2023 Basics of Genetic Inheritance Genotype vs phenotype Homozygous vs heterozygous Recessive traits vs dominant alleles Basics of genetics Two polynucleotide chains that coil into a double helix Each chain made of a sugarphosphate back bone and the following nucleotides: Adenine, thymine, guanine, cytosine Adenine pairs with thymine Guanine pars with cytosine Sequence of these nucleotides encodes genetic information Basics of genetics knowthese Structure of DNA allows for it to 4steps be tightly packaged and coiled into the nucleus Basics of genetics Gametes Basics of genetics DNA RNA RNA Protein Homozygous vs. heterozygous Allele 1 Allele 2 Locus for gene An allele is one of many different forms of a gene at a particular locus (location) If there are 2+ alleles that occur at an appreciable frequency, the gene is considered to be polymorphic Homozygous = when alleles are identical on homologous chromosomes Heterozygous = when alleles are not identical on homologous chromosomes Hemizygous = when there is only a single copy of a particular gene Homozygoesdom some Dominant vs. recessive alleles one of each Dominant allele: A single dominant allele will produce a dominant phenotype 2dam hetrozyogoes Recessive allele: Must have two recessive alleles to produce a recessive phenotype two recessive alleles in order to produce a phenotype Genotype vs. phenotype Genotype Environment Phenotype The phenotype is an observable trait or physical property that is, in part, determined by the genotype (aka genetic code) TL: DR; basics of genetic inheritance Structure of DNA allows for it to be tightly packaged and coiled into the nucleus Central dogma of genetics: DNA  RNA  protein Humans cells are generally diploid, meaning they have 23 pairs of chromosomes (except for gametes, they are haploid, meaning they have one copy of each chromosome) Each pair of chromosome is a called a homologous pair and they contain the same genes, although often the genes have slight variations between them Each of the same genes on the homologous chromosomes is called an allele If they are the same then that is called homozygous If they are different then that is called heterozygous Alleles can be dominant or recessive, and the inheritance of these determines what phenotype is expressed Patterns of Inheritance Autosomal dominant Autosomal recessive X-linked dominant X-linked recessive Penetrance vs expressivity Heterozygote advantage Genetic inheritance & family history Family history is has clinical utility as a proxy for genetic, environmental, and behavioral risks to health When asking family history we typically keep it to first and second degree relatives because overlapping genetic information is strongest between these types of relatives First degree relatives – a person’s parent, child or sibling Second degree relatives – a person’s grandparents, grandchildren, uncles, aunts, niblings, half-siblings Genetic inheritance & family history Grandparents (2nd degree) Parent (1st degree) Aunt (2nd degree) Autosomal dominant Features: Children (1st degree) Grandchildren (2nd degree) Diseases with AD inheritance patterns are rare. An offspring from an affected heterozygous parent will have a 50% chance of inheriting the affected gene. All offspring in an affected homozygous parent will be affected. Autosomal dominant Features cont.: Expression of the trait is expressed equally in both genetic sexes. Does not typically skip generations. Autosomal recessive Features: Expression of trait necessitates two copies of the affected gene. Carrier means that a person has a single copy of the affected gene. Chance of inheriting affected gene is equal between both genetic sexes. If both parents are heterozygous for the affected gene, approximately ¼ of offspring will be affected. Sex-linked inheritance A disorder that involves either the X or Y chromosomes. Y-linked disorders are rare because the Y chromosome contains relatively few genes. In X-linked disorders, individuals with XY chromosomes are always hemizygous: If they inherit the X-chromosome with an affected allele, they will express the disease X-linked dominant Features: Fragile X syndrome XX-parent to XY-offspring and XXparent to XX-offspring transmission can occur No XY-parent to XY-offspring transmission Usually there are more affected XX than affected XY 50% affected status among siblings of affected parent angeniers X-linked recessive I Features: Duchenne muscular dystrophy More common in XY. No XY-parent to XY-offspring transmission. All XX-offspring of an affected XYparent will have affected allele (which means approximately 50% of their XY-offspring will be affected). Affected alleles can be transmitted through a series of XX carriers, causing the appearance of a skipped generation. Phenotype variability Penetrance: proportion of genotypes that actually show expected phenotypes is called penetrance. Expressivity: the degree to which phenotype expression differs among individuals. Heterozygote advantage Refers to a theory that an organism with two different alleles of a particular gene (heterozygous) has greater fitness than one how is homozygous. Example: sickle cell disease (resistance to malaria) Example: cystic fibrosis (resistance to cholera, typhoid) TL: DR; patterns of inheritance In AD, only one copy of the affected allele is needed to cause phenotypic expression Offspring have a 50% chance of inheriting the affected allele from a parent who is heterozygous or 100% chance if the parent is homozygous Disease does not skip generations In AR, two copies of the affected allele are needed to cause phenotypic expression Both parents must be at least heterozygous for the affected allele (carries) in order for offspring to inherited two mutated copies of the allele In X-linked dominant Transmission occurs through XX-parent to both XX and XY-offspring No XY-parent to XY-offspring transmission In X-linked recessive More common in XY-offspring Can appear to skip a generation because XX may be carriers Penetrance (proportion of genotypes that actually show expected phenotypes) is not the same as expressivity (the degree to which phenotype expression differs among individuals) Heterozygote advantage is a theory that heterozygosity sometimes increases fitness and survivial Epigenetics Types Significance Epigenetics Epigenetics are chemical modifications of DNA sequences or RNA that alter the expression of genes, resulting in disease and phenotypic variations. Epigenetic changes can be reversible and they do not change DNA sequence. Types: DNA methylation Histone modification Microribonucleic acids (miRNAs) DNA methylation Attachment of a methyl group to (usually) a cystine base that is followed by a guanine base. Causes a gene to become transcriptionally inactive or silent. Heavy methylation in the promotor region of a gene decreases the likelihood it will be transcribed into mRNA. Histone modifications Histone acetylation  an open chromatin structure that is accessible to transcription factors, which increases gene expression. Histone methylation  mostly enhances transcription. Histone phosphorylation  required for compaction of chromatin, which decreases gene expression. Microribonucleic acids (miRNA) miRNA are small, RNA molecules that do not code for a protein. Involved in post-transcriptional regulation of gene expression. miRNAs bind to target mRNAs: Down-regulate their stability and/or translation Cause their degradation Epigenetics Epigenetics have a normal role in directing cell development into different cell types. Epigenetic changes vary throughout the lifespan and are associated with aging process. External factors influence epigenetic changes (i.e., tobacco smoke, nutrition) Epigenetics They are related to development of disease (i.e., cancer development) DNA methylation patterns, miRNA sequences can be inherited. Dutch Famine 1944-1945 TL: DR; epigenetics Epigenetics are chemical modifications of DNA sequences or RNA that alter the expression of genes, resulting in disease and phenotypic variations, but they don’t modify the actual DNA sequence DNA methylation: attachment of a methyl group to the DNA, causing a gene to become transcriptionally inactive or silent. Histone modification: acetylation  increases gene expression, methylation  mostly enhances transcription, phosphorylation  decreases gene expression. miRNAs bind to target mRNAs and down-regulate their stability and/or translation, or cause their degradation Epigenetic change are a normal part of cell development but they can be the cause of increase in risk of disease development and they can be inherited. Errors in DNA Related to Genetic Inheritance DNA mutations Chromosomal aberrations Nondisjunction DNA mutations Point mutations occur when a single base is inserted, deleted, or changed within a DNA (or RNA) sequence. Usually occurs during DNA happens replication. in replication Mutagens increase the rate of mutation. Most mutations occur in non-coding portions of the genome. Mutations in promotor or coding regions may have significant implications. AKA single-nucleotide polymorphism (SNP) DNA mutations Types of point mutations Silent – occurs when the change of a base in a coding region of a gene does not affect the sequence of amino acids that make up the protein for which it encodes. Result is usually nothing serious. DNA mutations Types of point mutations Nonsense – occurs when the change of a base in the coding region of a gene results in a premature stop codon in DNA or a nonsense codon in the transcribed RNA. Result can be beneficial (unlikely), neutral (unlikely), deleterious (more likely) Example: cystic fibrosis DNA mutations Types of point mutations Missense – occurs when the change of a base in the coding region of a gene results in a codon in the DNA sequence that codes for a different amino acid. Result is hard to predict due to difficulty in determining how the function of the resultant protein will be impacted. Example: sickle cell DNA mutations Types of point mutations Frameshift – occurs when there is an insertion or deletion of bases and it results in a shifting of the reading frame, thus impacting the entire gene sequence following the mutation. Result is more likely to be serious or catastrophic Example: Tay-Sachs Chromosomal aberrations Euploidy – having a chromosome number that is an exact multiple of the haploid number. Diploid cells are euploid cells Chromosomal aberrations Aneuploidy – having a chromosome number that is not an exact multiple of the haploid number. Trisomy – somatic cells contains three copies of one chromosomes Trisomy 21 Trisomy 18 Monosomy – somatic cells contain only one copy of any chromosome Turner syndrome XO Nondisjunction “Crossing over” Chromosomal aberrations Polyploidy – having more than one pair of homologous chromosomes. Rare in humans Can be due to polyspermy during fertilization, most often resulting in miscarriage or fetal demise Chromosomal aberrations Chromosome deletions Entire portions of a chromosome may be lost during DNA replication or during cross over in meiosis. May also be caused by chromosome breakage. Example: Cri du chat Chromosomal aberrations Chromosome duplications Extra copies of a chromosomal region are formed, resulting in different copy numbers of genes within that area of the chromosome. Example: Potocki-Lupski syndrome (17p11.2) Chromosomal aberrations Inversion Breakage of a segment of the chromosome, is repaired in the opposite orientation Often no significant clinical consequence Can impact fertility and can cause unbalanced chromosomes in gametes Chromosomal aberrations Translocation Chromosome breaks and fragmented pieces re-attach to different chromosomes. TL: DR; errors related to genetic inheritance Point mutations occur when a single base is inserted, deleted, or changed within a DNA (or RNA) sequence: they can be silent, nonsense, missense, or frame shift. Aneuploidy is having a chromosome number that is not an exact multiple of the haploid number (ex: Trisomy 21). Nondisjunction occurs during cell division and it can result in polyploidy, chromosome deletion, chromosome replication, chromosome inversion, chromosome translocation Genetics and Primary Care Genetics & primary care Advances in next-generation sequencing have improved how we identify genetic etiologies, while also increasing the demand for professionals qualified at interpreting these findings In the US, there is a significant shortage in the genetic services workforce 46% of families of children with special healthcare needs have difficulty accessing services Primary care providers, particularly in rural settings, serve as points of entry for patients to access appropriate care Genetics & primary care Cancer syndromes Hereditary breast and ovarian cancers (breast + ovarian) Lynch syndrome (colon + ovarian + endometrium) Cardiac syndromes Long Q-T syndromes (1:7000 individuals) Hereditary cardiomyopathy GI disorders Hereditary hemochromatosis Familial adenomatous polyposis Pulmonary disorders Alpha-1 antitrypsin deficiency ( a cause of COPD) Genetics & primary care “Red Flags” The patient is unusually young to have the condition The condition does not normally occur in patients of this sex There is an absence of typical environmental factors that are usually associated with the condition There is a strong family history of the condition The presentation is more severe than usual Genetics & primary care Reasons for referral to a genetic specialist Diagnosis/initial assessment in a symptomatic patient (or red flags) Further evaluation/management of a known diagnosis Risk assessment in an asymptomatic patient with a positive family history To aid in surgical and/or reproductive decision-making To identify appropriate transplant donor candidates in families with a genetic disorder Preconception screening Genetics & primary care Clinical Diagnosis Genetic Testing Management Considerations Genetic Counseling