麻省理工大学：遗传学（Genetics）讲稿_lecture31

Lecture 31: Genetic Heterogeneity and Complex Traits Allelic heterogeneity Nonallelic heterogeneity Twin studies Sib-pair analysis

Lecture 31: Genetic Heterogeneity and Complex Traits • Allelic heterogeneity • Nonallelic heterogeneity • r • Twin studies • Sib-pair analysis

Each of the heritable human traits that we have discussed in recent weeks is monogenIc invariably caused by mutation in the same gene Each of these traits was quite straightforward from a Mendelian perspective Sickle cell disease: autosomal recessive Phenylketonuria: autosomal recessive Huntington's disease: autosomal dominant genetic homogeneity all affected individuals have the same mutation in the same gene

Each of the heritable human traits that we have discussed in recent weeks is monogenic Each of these traits was quite straightforward from a Mendelian perspective: invariably caused by mutation in the same gene. Sickle cell disease: autosomal recessive Phenylketonuria: autosomal recessive Huntington's disease: autosomal dominant genetic homogeneity all affected individuals have the same mutation in the same gene

ALLELIC HETEROGENEITY cystic fibrosis(cF) autosomal recessive disorder affecting 1/2500 newborns in populations of European origin phenotype: sticky viscous secretions >obstruction of pancreas and airways> pancreatic insufficiency(treated with enzyme supplements)+ lung infections mapped to chromosome 7 by genetic linkage analysis in 1985 gene identified at molecular level in 1989: encodes a chloride channel protein >600 mutant alleles in the gene have been identified allelic heterogeneity Would such allelic heterogeneity affect the outcome of combining LOD scores from multiple families with affected children No, because all such families would show linkage to the same chromosomal locus

ALLELIC HETEROGENEITY cystic fibrosis (CF): • autosomal recessive disorder affecting 1/2500 newborns in populations of European origin • phenotype: sticky viscous secretions  obstruction of pancreas and airways  pancreatic insufficiency (treated with enzyme supplements) + lung infections • mapped to chromosome 7 by genetic linkage analysis in 1985 • gene identified at molecular level in 1989: encodes a chloride channel protein allelic heterogeneity Would such allelic heterogeneity affect the outcome of combining LOD scores from multiple families with affected children? No, because all such families would show linkage to the same chromosomal locus. • > 600 mutant alleles in the gene have been identified

TWO MUSCULAR DYSTROPHIES DUCHEYNNE BECKER

DUCHEYNNE BECKER TWO MUSCULAR DYSTROPHIES

retinitis pigmentosa(RP) degeneration of retina(accompanied by deposits of pigment in retina)) progressive visual impairment blindness population prevalence of 1/3,000 one of most common causes of blindness among middle aged in developed countries autosomal recessive inheritance in 84% of affected families autosomal dominant inheritance in 10% of affected families X-linked recessive inheritance in 6% of affected families At least 66 different genetic loci implicated but RP appears to be result of a single gene mutation in any given family, at least in most cases NON-ALLELIC HETEROGENEITY

retinitis pigmentosa (RP): • degeneration of retina (accompanied by deposits of pigment in retina)  progressive visual impairment  blindness • population prevalence of 1/3,000 • one of most common causes of blindness among middle aged in developed countries • autosomal recessive inheritance in 84% of affected families • autosomal dominant inheritance in 10% of affected families • X-linked recessive inheritance in 6% of affected families • At least 66 different genetic loci implicated but RP appears to be result of a single gene mutation in any given family, at least in most cases NON-ALLELIC HETEROGENEITY

How could one begin to genetically dissect a trait like RP that shows nonallelic heterogeneity? pproach 1: Linkage analysis on large families with many affected individuals Different families with RP may show linkage to different loci, combining LOD scores from different families might obscure rather than clarify the situation However, this trap can be avoided if one can identify a family with sufficient numbers of affected individuals (and informative meioses to provide, by itself. a lod score of 3 Approach 2: Direct search for mutations in candidate genes In some diseases, one can make good guesses as to the biochemical structures or pathways that are likely sites of causative mutations. In such cases, a direct search for mutations at the dNa sequence level in candidate genes"--can be an effective strategy--even in the absence of any prior genetic linkage analysis

How could one begin to genetically dissect a trait like RP that shows nonallelic heterogeneity? Approach 1: Linkage analysis on large families with many affected individuals. combining LOD scores from different families might obscure rather than clarify the situation. However, this trap can be avoided if one can identify a family with sufficient numbers of affected individuals (and informative meioses) to provide, by itself, a LOD score of 3. Approach 2: Direct search for mutations in candidate genes. In some diseases, one can make good guesses as to the biochemical structures or pathways that are likely sites of causative mutations. In such cases, a direct search for mutations at the DNA sequence level in "candidate genes" -- can be an effective strategy -- even in the absence of any prior genetic linkage analysis. Different families with RP may show linkage to different loci

This candidate gene" approach will become increasingly prominent given Complete sequence of human genome Complete sequence of human genome(rough draft published in 200 reference grade sequence expected in 2003) Falling cost of sequencing Perhaps 10 years from now, scientists will routinely sequence the entire genomes of individuals with unexplained phenotypes

This "candidate gene" approach will become increasingly prominent given: • Complete sequence of human genome • Falling cost of sequencing Complete sequence of human genome (rough draft published in 2001; reference grade sequence expected in 2003) Perhaps 10 years from now, scientists will routinely sequence the entire genomes of individuals with unexplained phenotypes

r= coefficient of relationship between two individuals likelihood of sharing by descent a given allele at a given locus expected proportion of all alleles (at all genes)that two individuals share by descent coefficient of relationship, r inbreeding coefficient, F likelihood that an individual is homozygous by descent at a given locus Relationship degree Parent-child 1st 1/2 Siblings 1/2 Aunt/niece 2nd 1/4 First cousins 3rd 1/8

r = coefficient of relationship between two individuals = likelihood of sharing by descent a given allele at a given locus = expected proportion of all alleles (at all genes) that two individuals share by descent coefficient of relationship, r ≠ inbreeding coefficient, F (likelihood that an individual is homozygous by descent at a given locus) First cousins Aunt/niece Siblings Parent-child Relationship degree r 1st 1/2 1st 1/2 2nd 1/4 3rd 1/8

Cleft lip is a common birth defect. Its incidence in the general population is about 0.001, but relatives of affected children are at higher risk Relatives of affected Risk(relative to degree affected child general population Sibs X40 Children 3.5 X35 Aunts and uncles 2nd 0.7 Nephews and nieces 2nd 0.8 First cousins 3rd 0.3 x8 Are these findings consistent with autosomal dominant inheritance of cleft lip? No, because the percentages of 1st and 2nd degree relatives who are affected are too low(would expect 50% and 25%, respectively) Are these findings consistent with autosomal recessive inheritance of cleft lip? lo, because the percentage of affected siblings is too low(would expect 25%)and because the risk in children is nearly as high as that in siblings

Cleft lip is a common birth defect. First cousins Nephews and nieces Aunts and uncles Children Sibs Risk (relative to general population) degree % affected Relatives of affected child 1st 4.1 x40 1st 3.5 x35 2nd 0.7 x7 2nd 0.8 x8 3rd 0.3 x3 Are these findings consistent with autosomal dominant inheritance of cleft lip? No, because the percentages of 1st and 2nd degree relatives who are affected are too low (would expect 50% and 25%, respectively). Are these findings consistent with autosomal recessive inheritance of cleft lip? No, because the percentage of affected siblings is too low (would expect 25%) and because the risk in children is nearly as high as that in siblings. about 0.001, incidence in the general population is but relatives of affected children are at higher risk: Its

Phenotypic concordance in monozygotic(MZ; identical) and dizygotic(DZ; fraternal)twins MZ twins arise when a developing embryo(derived from one zygote fertilization of one egg by one sperm) splits into two parts each giving rise to a baby DZ twins arise from two separate but nearly simultaneous fertilization events Relationship degree Parent-child 1st 1/2 Siblings 1st 1/2 Aunt/niece 2nd 1/4 First Cousins 3rd 1/8 亿 Z twins 0 DZ twins 1st 1/2

Phenotypic concordance in monozygotic (MZ; identical) and dizygotic (DZ; fraternal) twins MZ twins arise when a developing embryo (derived from one zygote; fertilization of one egg by one sperm) splits into two parts, each giving rise to a baby DZ twins arise from two separate, but nearly simultaneous fertilization events. Parent-child 1st 1/2 Siblings 1st 1/2 Aunt/niece 2nd 1/4 First Cousins 3rd 1/8 DZ twins MZ twins Relationship degree r 0 1 1st 1/2