Complications of Mendelian Inheritance PDF

Complications of Mendelian s2c1 Inheritance Paul Dunn Learning Objectives Describe the difference between complete 1 dominance, incomplete dominance & co- dominance Name & define mechanisms which 2 complicate inheritance patterns (e.g....

Complications of Mendelian s2c1 Inheritance Paul Dunn Learning Objectives Describe the difference between complete 1 dominance, incomplete dominance & co- dominance Name & define mechanisms which 2 complicate inheritance patterns (e.g. pleiotropy, epistasis, etc.) Differentiate between: incomplete 3 penetrance & variable expressivity, mosaicism & chimerism Explain the mitochondrial mode of 4 inheritance  Complications  Clear-cut dominant/recessive relationship are not always observed  Pedigrees do not follow the basic rules of Mendelian inheritance  e.g. X-linked diseases  Often 2 or more genes influence a single phenotype  Polygenic  Phenotypes are often the result of both genetics & the environment within which genes are expressed   Types of Dominance  Relationship between gene products as seen in the phenotype of a heterozygote  Complete Dominance  Heterozygote has same phenotype as homozygote  Incomplete/Partial Dominance  heterozygote shows intermediate phenotype  Co-Dominance  heterozygote expresses both phenotypes Incomplete Dominance Petal colour in SnapdragonsColour dilution gene in horses Ch estnut (C C) Palamino (CCr C) Cremello (CCr CCr)  Co-Dominant Inheritance  ABO blood grouping BLOOD TYPE A BLOOD TYPE B  Three alleles A,B, O  A & B alleles show codominance A O B O  O allele is recessive to both A&B A B A O B O O O  6 genotypes  AA, AO, AB, BB, BO, OO BLOOD TYPE ABBLOOD TYPE A BLOOD TYPE B BLOOD TYPE O  4 phenotypes (CODOMINANT)  A, B, AB, O  Incomplete Penetrance  a.k.a. reduced or variable penetrance  Some apparently dominant alleles sometimes ‘skip a generation’  Individual has the mutant gene but does not express the disease phenotype  e.g. BRCA1 and BRCA2 mutations – breast or ovarian cancer  Incomplete Penetrance & XLR  Both present pedigrees that skip generations  XLR = predominantly affect males; skip exclusively through females  Incomplete penetrance = affected/skipping X-linked recessive Autosomal dominant with incomplete penetranc  Age-Dependant Penetrance  Also referred to as ‘late manifestation’  Not all genetic diseases are expressed at birth, the age of onset may be later in life  Gene mutations can influence the age of onset  Symptoms in later generations are often more severe & appear at progressively younger ages, phenomenon known as anticipation  e.g. Huntington disease  CAG repeat size correlates to age of onset & disease severity  Variable Expressivity  A dominant & fully penetrant mutant allele causes a disease in all individuals although the severity & expression vary considerably  e.g. Neurofibromatosis type 1  Café-au-lait spots → dermal neurofibromas http://dermatlas.med.jhmi.edu/derm/display.cfm?ImageID=1615578762 Incomplete Penetrance vs. Variable Expressivity  Loss-of-Function Mutations  Loss-of-function mutations are most often seen as recessive diseases, but can also seen in some dominant disorders 1. Haploinsufficiency  50% of the gene’s protein product is insufficient for normal function 2. Dominant Negative Mutations  Abnormal protein product interferes with the normal protein product  Haploinsufficiency  Only one functional copy of a gene is present Number Expressio of n level  The other copy is mutated functional alleles 2 100 Normal % phenotyp e  Single functional copy is unable to produce enough gene product (i.e. protein) to display the normal phenotype  Incomplete dominance 1 50% Disease Di veri  Disease phenotype is due to the absence of the se se t y as second functional allele NOT the presence of e the abnormal allele 0 0%  Therefore, loss of function  Dominant Negative Mutation  Only one functional copy of a gene is present  The other copy is mutated  Mutated protein antagonises the normal protein  Functional protein often exists as a dimer, tetramer, etc.  Results in inactive function - Therefore, loss of function  Disease phenotype is due to the presence of the abnormal allele NOT the absence of the second normal allele  Receptor Tyrosine Kinases  Receptor tyrosine kinases are monomeric cell surface receptors  When a ligand binds to their extracellular domain receptor dimers form  Dimerization causes receptor activation p p p p p p  by autophosphorylation of intracellular domain p p  This allows other proteins to bind to the intracellular domain  Receptor Tyrosine Kinases Ligand Normal Mutated RTK RTK p p pp p p p p Dominant Negative  Epistasis  Where the mutation of one gene interferes or masks the phenotypic expression of another gene, also known as modifier genes  Example: Widow’s peak & baldness  In humans, a widow’s peak is dominant (HH or Hh) to a straight hair line (hh)  The gene for complete baldness is recessive (bb)  If you have the gene for complete baldness (bb) it doesn’t matter whether you have the alleles for a widow’s peak (H_) or not (hh)  Pleiotropy  A pleotropic gene is one that influences multiple (apparently unrelated) phenotypic traits  e.g. Marfan syndrome  Caused by a mutation in FBN1 gene which encodes fibrillin, a protein important in connective tissue  Impacts the skeleton, heart, blood vessels, eyes, lungs, skin  Pleiotropy  A pleotropic gene is one that influences multiple (apparently unrelated) phenotypic traits  Can be shown as different traits plotted on the same pedigree Marfan Syndrome & Pleiotropy  Genetic Heterogeneity  Single phenotype may be caused by any one of a multiple number of mutations in the same gene (allelic) or different genes (locus)  Allelic Heterogeneity  Different mutations within a single gene (multiple alleles) can cause the same phenotypic expression  e.g. cystic fibrosis; >1,000 known CFTR mutant alleles  Locus Heterogeneity  Disease is caused by a mutation in one of a many unrelated genes  e.g. retinitis pigmentosa; >38 genes; AD, AR, XL  Mosaicism & Chimerism  Individuals who have more than one genetically-distinct population of cells  Mosaic  Genetically different cells all arise from a single zygote - X chromosome inactivation in females - Mosaic Down syndrome (46,XX/47,XX+21)  Chimeria  Genetically different cells arise from more than one zygote - Fusion of twin embryos - Maternal-foetal trafficking - Organ or stem-cell transplants  Females are Genetic Mosaics with respect to genes on X Chr Mosaicism vs. Chimerism Strachan & Read Figure 4-1  You Are Your Own Twin  Lydia Fairchild & Karen Keegan  http://abcnews.go.com/Primetime/shes-twin/story?id=2 315693  How a Man’s Unborn Twin Fathered His Child  http://time.com/4091210/chimera-twins/  Genomic Imprinting  An epigenetic process by which some genes are expressed based on the paternal or maternal allele  Leaves a sex-specific mark that is required for normal embryonic development  Non-expressed allele is transcriptionally silenced by methylation and histone modification  Thought to occur either prior to- or during gametogenesis  Different regions are marked dependant on sperm-forming or egg-forming tissues  Silenced alleles are said to be imprinted  Which allele is expressed is determined in a parent-of-origin-specific manner  e.g. only the maternally inherited allele is ever expressed, or vice versa  Prader-Willi Syndrome & Angelman Syndrome Jorde, Fig. 5-11  Gene/Environment Interactions  Phenotypes are often the result of both genetics & the environment within which genes are expressed  e.g. Temperature effects - Siamese cat fur colour - Heat-shock proteins  e.g. Nutritional effects - Phenylketonuria - Lactose intolerance  Polygenic & Multifactorial Diseases  Involves the interaction of many genes & environmental factors  e.g. most cancers, heart disease, diabetes, obesity, migraine, hypertension, Alzheimer, suicide, schizophrenia, bipolar disorder, alcoholism, osteoporosis, asthma, arthritis, etc.  Complicated further by:  Epistasis, incomplete penetrance, variable expressivity, pleiotropy, etc.  Extremely difficult to study/treat Mitochondrial DNA  Mitochondrial Inheritance  Mitochondria contain DNA  (circular, 16.5kb, 37 genes)  13 of these genes involved in oxidative phosphylation  Mitochondria are inherited maternally  Paternal mitochondria (from sperm) lost during fertilization  Role of the Mitochondrion  Critical role in ATP production (for energy)  Number of mitochondria in each cell varies (200-5,000 per cell)  Cells that require more energy (muscle, heart, brain) have more mitochondria  Mitochondrial Inheritance UNAFFEC AFFECTE AFFECT UNAFFEC TED D ED TED FATHER MOTHER FATHER MOTHER Affected females Affected males DO transmit the NOT transmit the disease to ALL disease to their their children children ALL CHILDREN ARE ALL CHILDREN ARE AFFECTED UNAFFECTED  Heteroplasmy  Cell contains mitochondria with both normal & mutant mtDNA  By chance some cells may receive more or less defective mitochondria  Mitochondrial disease severity is highly variable  degree of heteroplasmy can also vary from affected organ to organ Youssoufian, H., Pyeritz, R. Mechanisms and consequences of somatic mosaicism in humans. Nat Rev Genet 3, 748–758 (2002). https://doi.org/10.1038/nrg9  Resources & Animations  Inheriting Genetic Conditions  http://ghr.nlm.nih.gov/handbook/inheritance  Genetic Dominance  http://www.nature.com/scitable/topicpage/genetic-dominance-genotype-phenotype-relat ionships-489  Penetrance & Expressivity  https://www.genomicseducation.hee.nhs.uk/blog/do-our-genes-govern-our-fate/  Chimeras & Mosaics  https://www.youtube.com/watch?v=eSMQcy5ReQQ  Mitochondrial Disease  https://www.youtube.com/watch?v=66Tjk8wtJYY  Texts:  Medical Genetics, Jorde et al, Chapters 4 & 5