Additional Inheritance Patterns and Pedigree Analysis PDF

Additional Inheritance Patterns and Pedigree Analysis BMS 532 MOLECULAR BIOLOGY AND GENETICS BLOCK 4 LECTURE 1  Objectives 1. Define the following terms: qualitative trait, quantitative trait, incomplete dominance, codominance, penetrance, expressivity, phenotypic plasti...

Additional Inheritance Patterns and Pedigree Analysis BMS 532 MOLECULAR BIOLOGY AND GENETICS BLOCK 4 LECTURE 1  Objectives 1. Define the following terms: qualitative trait, quantitative trait, incomplete dominance, codominance, penetrance, expressivity, phenotypic plasticity, epistasis, pedigree, first degree relative, second degree relative, and consanguinity 2. Explain the relationship between phenotypic variation and the number of genes involved in the phenotype 3. Identify phenotypic consequences of a particular gene or set of genes in terms of dominance and define inheritance from phenotypic outcomes observed from given mating(s) 4. Explain deviations from Mendel expectations based on genetic interactions 5. Connect general concepts in inheritance with evaluation of human inheritance and genetic disease 6. Apply the rules of inheritance to evaluate a pedigree and identify the most likely inheritance pattern AND individual genotypes from a family history (pedigree) 7. Generate a pedigree to analyze inheritance of a trait and assess the most likely outcomes for specific individuals 8. Compare and contrast the features and inheritance patterns of monogenic, polygenic, and complex traits and diseases NOTE: all images in this packet are derived from Essential Genetics (Jones and Bartlett Publishing) unless otherwise noted LO1, LO2 Deviations in Mendelian Inheritance In addition to sex-linked traits, there are many aspects of actual genetics that lead to deviations from expected Mendelian Inheritance Qualitative vs Quantitative Traits ◦ Qualitative refers to variation produced at a specific locus ◦ Fit into specific categories and match expected presence/absence deviations from Mendel ◦ Incomplete Dominance and Codominance ◦ Quantitative refers to the concept that some features are the compilation of multiple genetic (and potentially environmental) interactions ◦ Built by several genes contributing small effects on the overall phenotype In general, the number of phenotypes possible increases with the number of genes involved LO1, LO3, LO4 Incomplete Dominance Incomplete dominance = the phenotype of the heterozygous genotype is intermediate between the phenotypes of the homozygous genotypes Incomplete dominance is often observed when the phenotype is quantitative rather than discrete ◦ Discrete = fully distinct with no variations in expression ◦ Can also be quantified = level of expression correlates with observed phenotype LO1, LO3, LO4 Multiple Alleles/Codominance Codominance means that the heterozygous genotype exhibits the traits associated with both homozygous genotypes Codominance is more frequent for molecular traits than for morphological traits Multiple alleles = presence in a population of more than two alleles of a gene ABO blood groups are specified by three alleles IA, IB and IO IA and IB are codominant, while both IA and IB are both fully dominant to IO LO1, LO3, LO4 Multiple Alleles/Codominance: Blood Typing A Summary of Expression: B B A ◦ IA IA = type A ◦ blood type O genes; no antigens on RBC and produce both anti-A and anti-B antibodies in serum B B ◦ IB IB = type B ◦ blood type A genes; A-antigen on RBC and produce anti-B antibodies in serum ◦ IO IO = type O ◦ IA IO = type A ◦ blood type B genes; B-antigen on RBC and produce anti-A antibodies in serum A A ◦ IB IO = type B ◦ blood type AB genes; both A- and B-antigens on RBC and produce neither type of antibody in serum ◦ IA IB = type AB LO1, LO3, LO4 Evaluating Dominance When determining the type of expression it is helpful to consider what the gene encodes If the product made by the gene will ultimately: ◦ form a structure: it will likely be clearly present or absent (full dominance) ◦ Produces a compound that prevents expression of other compounds (full dominance) ◦ Produces a pigment that can mix with other pigments but remain distinct (codominance) ◦ Produces a pigment that always mixes (incomplete dominance) Example: SBEI enzyme: Co- or Incomplete? INCOMPLETE DOMINANCE: the heterozygote is intermediate between the two homozygotes LO1, LO3, LO4 Functional Consequences of Genes Protein levels can significantly influence cellular function Many recessive genes codes for enzymes which carry out specific steps in biochemical pathways ◦ Mutations which alter the structure of genes block enzyme production if BOTH copies of the gene are defective Gene Dosage Considerations: ◦ For some genes reduction of gene product by ½ in the heterozygote may be physiologically significant; especially for structural proteins = DOMINANT disorders ◦ Heterozygotes (Ww) may still produce sufficient gene product to display dominant phenotype = genotype carrier for recessive version LO1, LO2, LO3, LO4 Further Linking Genotype with Protein Expression and Phenotype Variation in the phenotypic expression of a particular genotype may happen because other genes modify the phenotype or because the biological processes that produce the phenotype are sensitive to environment Environment Affects Expression Variable expressivity refers to genes that are expressed to different degrees in different individuals, e.g.: severity of an inherited disease can be on a spectrum Incomplete penetrance means that the phenotype predicted from a specific genotype is not always expressed, e.g.: individual inherits mutant gene but shows no effect Basically, ◦ Penetrance = whether ◦ Expressivity = to what degree LO1, LO3, LO4 Epistasis Epistasis refers to any type of gene interaction that results in the F2 dihybrid ratio of 9:3:3:1 being modified into some other ratio In a more general sense, it means that one gene is masking the expression of the other Flower color in peas: formation of the purple pigment requires the dominant allele of both the C and P genes: the F2 ratio is modified to 9 purple:7 white  Modified Ratios For genes A and B Blue = traditional dom/dom phenotype Pink = traditional dom/rec phenotype Green = traditional rec/dom phenotype Yellow = traditional rec/rec phenotype LO1, LO3, LO4  EPISTASIS There are nine possible dihybrid ratios when both genes show complete dominance Examples: 9:7 occurs when a homozygous recessive mutation in either or both of two different genes produces the same phenotype 12:3:1 results when a dominant allele of one gene masks the phenotype of a different gene 9:3:4 is observed when homozygosity for a recessive allele masks the expression of a different gene LO1, LO3, LO4 LO1, LO2, LO3, LO4 Quantitative Traits and Phenotypic Plasticity Phenotypic plasticity = ability of multiple phenotypes to be encoded by the same genotype ◦ Flexibility of the phenotype in response to environmental or external cues If environmental factors are inducing or reducing expression of the genes associated with a given phenotype, then in different environments there will be different phenotypes This has a nice connection with epigenetic variation in hyacinths where changes in environment induce changes in petal color (environment induces changes in methylation) ◦ Regular soil = pink flowers ◦ Soil + additional aluminum sulfate = blue flowers ◦ Particular implications for invasive plant species as they enter and then take over a niche Epigenetic considerations such as this are also relevant in people: severity or alleviation of symptoms Human Genetic Analysis: Family History & Pedigrees FAMILY HISTORY PROVIDES A TREMENDOUS AMOUNT OF ESSENTIAL MEDICAL INFORMATION PARTICULARLY IN GENETICS LO5, LO6, LO7 Pedigree Analysis In humans, pedigree analysis is used to determine individual genotypes and to predict the mode of transmission of presumably monogenic traits Pedigree analysis is a detailed family medical history and is vital to Maternal- Fetal Medicine ◦ Probability analysis in humans ◦ RISK ASSESSMENT Can be used to define expected inheritance and narrow down likely causes as well as best individuals to evaluate further ◦ Best to study individuals at greatest risk rather than just test everyone For more information on pedigree nomenclature and standard practices see: Journal of Genetic Counseling, Volume: 31, Issue: 6, Pages: 1238-1248, First published: 15 September 2022, DOI: (10.1002/jgc4.1621) LO5, LO6, LO7 Pedigree Analysis Each pedigree should be composed of at least 3 generations to derive meaningful family medical history for risk analysis Age of disease onset is critical to identification of risk for complex diseases and corresponding plans for screening First-degree relatives are those of immediate familial connection and up to 50% genetic information in common (mom, dad, full siblings, children) Second-degree relatives are those of next interest and include one level removal of genetic connection with potential for up to 25% genetic information in common (grandparents, aunts/uncles, nieces/nephews, half-siblings, grandchildren) Third degree relatives have fewer genes in common with roughly 12.5% similarity expected (i.e. first cousins, great grandparents, etc…) LO5, LO6, LO7, LO8 Features of Monogenic Diseases RARE and SEVERE Selective pressure tends to eliminate the dominant form of this type of deleterious gene trait ◦ fast and effective means of removing dominant mutations from the gene pool When DOMINANT, phenotype tends to display or develop after sexual maturity ◦ Consequence of selective pressures They also persist due to being masked in the heterozygote (RECESSIVE) or exhibiting a variable phenotype (incomplete dominance or penetrance) Carriers will pass on the trait without exhibiting the phenotype (only defined as carrier when NOT exhibiting the phenotype) Increased expectations of observation of recessive traits in situations ofconsanguinity LO5, LO6, LO7 Autosomal Dominant Dominant phenotypic traits usually appear in every generation of a pedigree About 1/2 the offspring of an affected individual are affected The trait appears nearly equally in both sexes if autosomal EXAMPLE: Huntington disease ◦ A progressive nerve degeneration, usually beginning about middle age, that results in severe physical and mental disability and ultimately death ◦ The trait affects both sexes ◦ Every affected person has an affected parent ◦ ~1/2 the offspring of an affected individual are affected  FYI: Huntington’s Disease (HD) Rare DOMINANT genetic disorder that causes the breakdown of nerve cells in the brain Results in severe cognitive decline Most individuals develop signs and symptoms in their 40s and 50s; early onset can occur before the age of 20 for severe cases (homozygotes) Average Signs and symptoms ◦ Movement disorders ◦ Cognitive disorders ◦ Psychiatric disorders 1 in 10,000 individuals in the USA HD HD Approximately 16% of cases are juvenile Huntington’s Negi et. al. (2014) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4223233/ LO5, LO6, LO7 Autosomal Recessive Analysis of patterns of transmission of recessive genes is used to identify carriers of recessive traits which cannot be determined by direct phenotypic analysis Recessive traits can occur in individuals whose parents are phenotypically dominant = Heterozygous Carriers ◦ NOTE: If you have the dominant allele of a dominant trait you have the trait, you are NOT a carrier. The only time the carrier designation can be used properly is if you have the allele but do NOT exhibit the trait. EXAMPLE: Albinism ◦ Absence of pigment in the skin, hair, and iris of the eyes. The trait affects both sexes ◦ Most affected persons have parents who are not themselves affected; the parents are heterozygous carriers ◦ Approximately 1/4 of the children of carriers are affected ◦ The parents of affected individuals are often relatives  Average FYI: Cystic Fibrosis Mutation in CF gene on Chromosome 7 ◦ The Cystic Fibrosis Transmembrane Regulator (CFTR) ◦ Leads to production of abnormal mucus ◦ Excessively thick and sticky Affects secretory glands including the mucus and sweat glands 15-year-old girl with cystic fibrosis Greatest negative affect on function of the lungs; although it also affects the pancreas, liver, intestines, sinuses, and sex organs Signs and Symptoms ◦ Baby may “taste” sweaty when kissed or fail to pass stool at birth ◦ Most happen later in life (~ age 5) due to the accumulation of affects ◦ Most other symptoms develop due to affects on respiratory system and digestive system Most common in the USA Incidence in Live Births ◦ 1 in 2,000 (Caucasian); ◦ 1 in 17,000 (African-American); ◦ 1 in 90,000 (Asian) 1 in 29 Americans is a carrier (frequently without knowledge) https://pubs.rsna.org/doi/10.1148/radiol.10092307 Vult von Steyern and Bjorkman-Burtscher (2013) Insights Imaging LO5, LO6, LO7 X-linked Dominant As with autosomal dominant, every generation of the pedigree is expected to exhibit the trait Disproportionate male to female ratios (typically more females showing the trait) ◦ Affected males cannot have completely unaffected daughters ◦ Males can only be affected if their mothers were or if there is inappropriate inheritance from the paternal source ◦ Some X-linked dominant disorders show male lethality therefore a even more disproportionate number of affected individuals will be female Role for X-inactivation to improve phenotypic outcomes EXAMPLE: X-linked lissencephaly https://www.cancer.gov/publications/dictionaries/genetics-dictionary/def/x- linked-dominant-inheritance LO5, LO6, LO7 X-linked Recessive As with autosomal recessive, the condition is expected to be more rare Can involve female carriers Disproportionate male to female ratios (typically more males showing the trait) ◦ Affected females cannot have completely unaffected sons ◦ Affected males cannot pass the trait to their sons (in the absence of errors or other complex mutations) Role for X-inactivation to improve phenotypic outcomes EXAMPLE: Hemophilia A LO5, LO6, LO7, LO8 Actual Complexity of Monogenic Traits In humans in particular, no human trait is truly monogenic as there are always complicating factors including ◦ Environment ◦ Lifestyle ◦ Genetic interactions ◦ Penetrance and Expressivity LO5, LO8 Features of Polygenic and Complex Diseases Tend to arise from less severe mutations in multiple genes These genes can be actors in the same metabolic pathway or across multiple pathways important to a particular activity Gene linkage analysis and whole genome analysis are utilized to identify which genes are working together to result in a disease phenotype LO5, LO8 Complex Diseases Definition: ◦ Diseases caused by a combination of genetic, environmental, and lifestyle factors Most human diseases fall into this category SPECTRUMS: phenotypes fall on a range of options and consequences are not necessarily a guarantee or can be modified EXAMPLES: ◦ Congenital defects ◦ Adult-onset diseases LO5, LO8 Inheritance and Disease Development for Polygenic and Complex Disorders Complex conditions/diseases/disorders do NOT follow Mendelian inheritance Do not obey the rules of dominant and recessive in the same manner as monogenic These arise from multiple genes (polygenic) AND often indeterminate factors working together Affected individuals may be born to unaffected parents with no familial history ◦ Can be truly de novo = the result of new mutation ◦ Can be due to the first mating between carriers with the right additional requirements in place LO5, LO8 Inheritance and Disease Development for Polygenic and Complex Disorders Single gene disorders can provide valuable insight into genes involved in complex disorders ◦ Aid in identification of genes involved based on phenotypic similarities Inheritance is of associated genes; indicates only a partial risk ◦ The risk may be significant but it is still just an increase in risk ◦ Example: Cancer predisposition genes Disease development is dependent on environment and lifestyle LO5, LO8 Defining Environment Environment can be our external world-wide exposures ◦ The air we breathe, the food we eat, etc… It can also be: ◦ Our overall internal systems (temperature, chemical compositions, etc) ◦ Our individual cells (cell-to-cell interactions, antibody production, ENZYMATIC ACTIVITY, etc) Questions An individual inherits a pathogenic variant of a gene: ◦ If the pathogenicity is inherited in an autosomal dominant manner, what are the possible genotypes of the parents? (LO3, LO5, LO6) ◦ If the pathogenicity is inherited in an autosomal recessive manner, what are the possible genotypes of the parents? (LO3, LO5, LO6) ◦ Draw the pedigree adding in the following features: the individual is male, neither parent is affected, there are 3 siblings as follows: male with, male without, female without. The maternal grandfather was affected but the maternal grandmother was not (no additional relatives on maternal side). Neither paternal grandparent was affected and one additional child was also not affected. What would you expect for manifestation of a genetic disorder if disease phenotype is influenced by environment and no environmental triggers are present? (LO5, LO8)