Unification of biometrics and mendelian genetics RA Fisher was a 20th century genius who made fundamental contributions to the fields of statistics and biology. In statistics, he developed analysis of variance(ANOVA), the maximum likelihood method for estimating the values of parameters based on experimental data, permutation testing to estimate statistical significance(P-values), and exact tests for estimating statistical significance in small samples In biology, Fisher(together with Sewall Wright and Sir Ronald A Fisher(1890-1962) J.B.S. Haldane) is considered one of the founders English statistician, evolutionary of the "Modern Evolutionary Synthesis, " which unified biologist, geneticist, eugenicist; Darwin s theory of natural selection with mendel- Published: The correlation Between relatives on the inspired concepts of modern genetics. Among many supposition of Mendelian contributions, Fisher was the first to propose the idea Inheritance”in1918 of heterozygote advantage to explain the persistence of harmful genetic variants in certain populations
Unification of biometrics and Mendelian genetics Sir Ronald A. Fisher (1890-1962) English statistician, evolutionary biologist, geneticist, eugenicist; Published: “The correlation Between relatives on the supposition of Mendelian Inheritance” in 1918. RA Fisher was a 20th century genius who made fundamental contributions to the fields of statistics and biology. In statistics, he developed analysis of variance (ANOVA), the maximum likelihood method for estimating the values of parameters based on experimental data, permutation testing to estimate statistical significance (P-values), and exact tests for estimating statistical significance in small samples. In biology, Fisher (together with Sewall Wright and J.B.S. Haldane) is considered one of the founders of the “Modern Evolutionary Synthesis,” which unified Darwin’s theory of natural selection with Mendelinspired concepts of modern genetics. Among many contributions, Fisher was the first to propose the idea of heterozygote advantage to explain the persistence of harmful genetic variants in certain populations
The combined effects of multiple genes can produce normal distributions for quantitative traits (A)one locus (C) three loci AABbcC AAbbCc AAbbcc AaBBcc aaBBCC AaBbcc aaBBCc AAbbCc AabbCc AabbCC AABBcc aaBBcc aaBbCC AaBbCC a BbCc AaBbCc AaBBCc Aabbcc aabbcc AABbCC AABBCc aaBbcc AAbbCc aaDo AaBBCC aabbcc AABBCC 708090100110120130 708090100110120130 (B)two loci (D) many loci 8 aab 708090100110120130 708090100110120130
The combined effects of multiple genes can produce normal distributions for quantitative traits
B. Phenotypes in populations Familial aggregation of disease Disease risk as a quantitative trait Factors that obscure patterns of inheritance
B. Phenotypes in populations • Familial aggregation of disease • Disease risk as a quantitative trait • Factors that obscure patterns of inheritance
Familial aggregation of disease Relative risk Prevalence of the disease among the relatives of an affected person Prevalence of the disease in the general population Concordance and allele sharing among relatives Genotype of sib #1 A1A4 A2A3 A2A4 AlA2 Degree of Relationship and Alleles in Common AlA3 Proportion of Alleles in A1 Relationship to proband Common with Proband M A2A3 First-degree relative 12 Second-degree relative A2A40 Third-degree relative 1/8 0. 25 (2 shared alleles)+0.5(1 shared allele +0.25 (0 shared alleles)=1 shared allele (average). One-of-two alleles shared 50% shared alleles
Familial aggregation of disease • Relative risk • Concordance and allele sharing among relatives Prevalence of the disease among the relatives of an affected person Prevalence of the disease in the general population lr = 0.25 (2 shared alleles) + 0.5 (1 shared allele) + 0.25 (0 shared alleles) = 1 shared allele (average). One-of-two alleles shared = 50% shared alleles
Correlations between risk of developing schizophrenia and the degree of relatedness among relatives GENES SHARED eral popul 125%(1/8) first cousins 3rd degree relatives uncles/aunts nephews/ nieces ■25%(1/4 2nd degree relatives grandchildren half siblings 50%(1/2) nst degree relatives arents children fraternal twi identical twins 10 RELATIONSHIP TO PERSON RISK OF DEVELOPING SCHIZOPHRENIA WITH SCHIZOPHRENIA
(1/2) (1/4) (1/8) Correlations between risk of developing schizophrenia and the degree of relatedness among relatives