1、第七章 群体遗传,概要,什么是群体遗传学？ 群体遗传组成 基因频率和基因型频率。 Hardy Weinberg 平衡定律。 影响基因频率的因素。 近亲婚配及其对群体遗传素质的影响。,Population/Gene Pool,Population = group of organisms of the same species living in the same geographical area and mating with each other/群体 = 属于一个物种、生活在同一地区、并能相互杂交的个体群，是物种的基本结构单位。,Gene pool = all alleles in po
2、pulation/基因库 = 一个群体所具有的全部遗传信息，即含有在特定位点的全部等位基因。,Population Genetics,Study of Genetic constitute of Population and its variation./研究群体的遗传组成及其变化规律的学科 Distribution of genes in population, maintenance of gene frequencies and genotype frequencies and their variations./研究群体中基因的分布、基因频率和基因型频率的维持和变化的科学。,对于医学而
3、言，群体遗传是要探讨遗传病的发病频率、遗传方式、致病基因频率及其变化的规律，以了解遗传病在群体中的发生和散布的规律，为预防、监测和治疗遗传病提供重要的信息和措施。因此有人又称之为遗传流行病学（genetic epidemiology）。,The Area of Population Genetics focuses on,Estimation gene frequency and genotype frequency/怎样估计群体的基因频率和基因型频率? Factors affecting gene frequency/哪些因素可影响基因频率? How to improve genetic q
4、uality of offsprings/怎样增进我们子孙后代的遗传素质?,Genetic constitute of Population 群体的遗传组成,Genetic variations among different populations in the same species are built on difference in allele frequencies./由于同一物种内不同群体间的遗传变异主要在于基因频率的差异, 所以基因频率是群体遗传组成的基本标志。,Genetic constitute of Population,= Distributions or ratio
5、s of genes/alleles in a population/群体的遗传组成 = 各种基因在群体里的分布或所占的比例。,Genotype & Allele Freqs,Genotype frequency = proportion of individuals in a population with a specific genotype./基因型频率 = 指特定基因型的个体在群体中所占的比率。 Allele frequency = proportion of alleles in a population./基因频率 = 指某一基因在群体出现的频率，即一种等位基因占该座位全部等位基
6、因的比率。同一位点的全部等位基因的频率之和为1。,Alleles Genotypes A a AA Aa aaFreqs p q D H R,Freq(A)：p = D + 1/2H Freq(a)：q = R + 1/2H,Calculating Allele Frequencies from Genotype Frequencies,Freq(LM)：0.03 + 1/2 0.296 = 0.178 Freq(LN)：0.674 + 1/2 0.296 = 0.822,EXAMPLE:,Hardy-Weinberg Equilibrium,Assuming the Hardy-Weinbe
7、rg conditions,Random mating (individuals mate independent of their genotype) No mutation, no selection, no migration Large population size (genetic drift can be ignored) Allele frequencies the same in both sexes,Then, HW says:,Allele frequencies will remain constant over time./基因频率将代代保持不变。 Genotype
8、frequencies will also keep constant over generations after one generation of random mating./一代随机交配以后基因型频率也将代代保持不变。,Verification of HW Law,Consider a single autosomal locus with two alleles, A and a, whose population frequencies in both sperm and eggs are the same. p = frequency of allele A (dominant
9、) q = a (recessive) p + q = 1. And the genotypes frequencies are: Genotype: AA Aa aa Frequency: D H R,Assume If： D = 0.5, H = 0.4 and R = 0.1 Then， p = D+ H = 0.5 + 0.2 = 0.7 q = H + R = 0.2 + 0.1 = 0.3,p2 AA,a,Female gametes,Male gametes,A,A,q,p,a,p,q,pq Aa,q2 aa,pq Aa,(p+q)2 = p2+2pq+q2 = 1,Random
10、 Mating = Gametes Combine at Random.,So， p1 = D1 + H1 = p2 + pq = p(p+q) = p. By the same token, q1 = q,p2 AA,a,Female gametes,Male gametes,A,A,a,p=.7,q=.3,pq Aa,q2 aa,pq Aa,(p+q)2 = p2 + 2pq + q2 = 1,.49,.21,.09,.21,p=.7,q=.3,AA,Aa,aa,So, p1 = D1 + H1 = 0.49 + 0.21 = 0.7 = p q1 = R1 + H1 = 0.09 + 0
11、.21 = 0.3 = q,D1 H1 R1,What About the Next Generation?,p2 = p12 + p1q1 = p1 (p1+q1) = p1 = p D2 = p12 = p2 = D1 D,p12 AA,p1q1 Aa,q12 aa,p1q1 Aa,.49,.21,.09,.21,p2 = . 49 + .21 = 0.7,q2 = .0 9 + .21 = 0.3,A p1 a q1,A p1a q1,By the Same Token,pn = pn-1 = = p1 = p qn = qn-1 = = q1 = q. And Dn = Dn-1 =
12、D1 Hn = Hn-1 = H1 Rn = Rn-1 = R1,X-linked HW,X-linked genes are a special case (because males have only one X-chrm) Genotype frequencies among males are the same as allele frequencies:Frequency of XAY males = pFrequency of XaY males = q And genotye & gene frequencies among females are the same as au
13、tosomal alleles,Example,One out of every 20 men has red-green colorblindnessWhat is the incidence of red-green colorblindness among women?,Answer:,q = Rm = 1/20 (given)Rf = q2 = 1/400 = incidence in femalesHf = 2pq 1/10 = female carrier freq.,Multiple allele HW,Hardy-Weinberg frequencies can be exte
14、nded to multiple alleles: Frequency of any homozygote =square of allele frequency/纯合子频率 = 基因频率的平方 Frequency of any heterozygote = 2 X product of allele frequencies/杂合子频率 = 2 X 等位基因频率之积,What We Learn from HW?,揭示了基因频率和基因型频率的遗传规律。预示了在一个大的群体中，种群的遗传特性能够保持相对的稳定。 阐明了基因频率和基因型频率间的一般关系，从而为在各种情况下计算群体的基因频率提供了依据
15、。,Hardy Weinberg Law,can be used to find the freqency of recessive disease alleles in a population and carrier frequency,Application:,设某常染色体隐性遗传病受一等位基因A和a控制，基因型为aa的个体发病, 其发病率为R。 由Hardy-Weinberg定律：AA Aa aa p2 2pq q2,隐性基因纯合体发病：q2 = R,隐性基因频率：q = R1/2,显性基因频率：p =1-q =1-R1/2,杂合子的频率：H = 2pq,Example：尿黑酸尿症为常
16、染色体隐性遗传病，约1,000,000 儿童中有1个患儿，其发病率 = 0. 000 001。,尿黑酸尿隐性基因频率：q = R1/2 =（0.000 001）1/2 = 0. 001 正常显性基因频率：p = 1-q = 1 - 0.001 = 0.999 杂合子频率：2pq = 2 0.999 0.001 = 0.002,(p+q)2 = p2 + 2pq + q2 = 1HW equilibrium: allele freqs remain constant from generation to generation, under certain conditions.,Allele f
17、reqs,Genotype freqs,Gene pool,Hardy Weinberg Law:,A,a,AA,Aa,aa,Factors that Alter Gene Frequencies 影响基因频率的因素,Forces that can cause deviation from HW ratios,Non-random mating (e.g., inbreeding) Gene flow (e.g., migration) Genetic drift (small population) Mutation Natural selection,基因突变（Gene Mutation)
18、,是群体发生变异的根源。基因突变对于群体遗传组成的改变有两个重要的作用：首先，突变本身改变了基因频率；其次，突变又为选择提供了材料。,Mutation in Bacteria,Generation,I,p=0.6; q=0.4,p=0.4; q=0.6,在某一世代，基因的一个等位基因突变为另一个等位基因的频率称为突变率( mutation rate)。 以一对常染色体等位基因A、 a为例。A每代以频率突变为a，而a以频率v反向突变为A，最终达到平衡。,Consider freq(A) (p): A fraction (1-) of the A alleles do not mutate, wh
19、ile a fraction v of the a alleles mutate to A.,Hence, freq(A) at n+1 generation is:,P(n+1) = (1-)pn + vqn= (1-)pn + v(1-pn) = (1-v)pn + v So, p(n+1) = P(n+1) pn = v-(+v) pn When p(n+1） = 0; freq(A) reaches an equilibrium value:p = v/(+v),选择（selection）,自然选择（natural selection）和人工选择（artificial selectio
20、n）都是导致基因频率变化的重要因素，就人而言，导致基因频率变化的主要选择因素是自然选择。,适合度(fitness，f) 是指一个个体能够生存并把他的基因传给下一代的能力，用相对生育率来表示。,选择主要是通过增加和减少个体的适合度来影响基因平衡。或者说，当一个群体的不同个体的适合度不同时，选择就会发生作用。,Example： 据调查， 108个软骨发育不全的侏儒，共有小孩27人；而他们457个正常的同胞 ，共生育582个小孩。如果软骨发育不全患者生育能力与正常同胞相同，108人中应有多少孩子？,582 ( 108 / 457 ) = 137. 5 而现在实际只有27个孩子，此症的生殖适合度为：
21、f = 27 / 137. 5 = 0. 1963,选择作用的大小用选择系数(selective coefficient, S)来代表，是指某一基因型在群体中不利于生存的程度，用生育率降低的程度来表示: S1-f,例如，软骨发育不全症患者的选择系数是: S = 1- 0.1963 = 0.8037,选择压力对遗传平衡的影响,选择对遗传平衡的影响与选择作用的强度有关，遗传学中称之为选择压力（selective pressure）。选择压力越大，选择系数越高，引起的基因频率的变化越明显。,反之，如果选择压力降低则会使群体中的有害基因增加，即增加了群体的遗传负荷。所谓遗传负荷(genetic loa
22、d)是指一个群体由于有害基因的存在而使其适合度降低的现象。,Selection for/against recessive alleles is inefficient,When the allele is rare Why? - because then most recessive alleles are in heterozygotes Thus, rare disease-causing recessive alleles persist in the population in heterozygote carriers, even if they are lethal when h
23、omozygous,alleles in affected 2q2,alleles in carriers 2pq,=,q,p,=,q,(1-q),=,q,1,=,= 1/10,000; q = 1/100, ,q2,Carrier/Affected Ratio for an autosomal recessive disease,q2,2pq,Disease Incidence,Carrier Frequency,Ratio Carrier/Affected,Is modern medical science ruining our gene pool?,Does saving the li
24、fe of people with recessive genetic diseases decrease the fitness of our population?,homework,遗传漂变(genetic drift),小群体中或隔离人群中，基因频率的随机波动称为遗传漂变(genetic drift)。由于群体较小，所以等位基因在传递过程中会使有的基因固定下来而传给子代，有的基因则丢失，最终使此基因在群体中消失。,Drift in Bacteria,Generation,I,p=0.6; q=0.4,p=0.5; q=0.5,Why me?,遗传漂变的速率取决于群体的大小。群体越小，漂
25、变的速率越快，常常在几代甚至一代后即可出现基因的固定和丢失。,遗传漂变的方向无法肯定，但是范围却可以估计。假设有一个容量为N的群体，考虑常染色体的某一基因座位，A和a，其基因频率分别为p和q，则下一世代基因频率改变的方差为：Varp = pq/2N,中性突变 随机漂变学说,在分子水平上，仅很少一部分突变是有利的，多数突变是有害的、中性的。 自然选择是一种保存有利突变和消灭有害突变的进化过程。 大部分新突变都将消失，少量新突变的固定依赖于随机漂变。,在分子水平上，群体存在着巨大的遗传变异，造成丰富的遗传多态。 一个群体由最初的少数几个人逐渐发展起来，则最初的人群对后代存在着显著的影响，称为“奠基
26、者效应”（founder effect）。,迁移(migration),迁移又称移居，迁移的结果使不同人群通婚，彼此渗入外来基因，导致基因流动，可改变原来群体的基因频率，这种影响也称为迁移压力。,迁移压力的大小一般取决于：1. 迁出和接受群体间基因频率的差异。2. 每代移入个体（基因）的数量。 迁移压力的增强可使某些基因从一个群体有效地散布到另一个群体，称为基因流(gene flow)。,Migration in Bacteria,Generation,I,p=0.6; q=0.4,p=0.5; q=0.5,Example: 对味盲(苯硫脲的尝味能力缺乏, tt)的调查发现，在欧洲和西亚白人中
27、，味盲基因频率(t)= 0.60。在我国汉族人群中，味盲基因频率(t)= 0.30。而在我国宁夏一带聚居的回族人群中， 味盲基因频率(t)= 0.45。 可能原因：在唐代，欧洲和西亚的人，尤其是波斯人沿丝绸之路到长安进行贸易，以后又在宁夏附近定居，与汉族人婚后形成的基因流所致。,近亲婚配consanguineous marriage,在4代之内有共同的祖先者均属近亲，如果他们之间进行婚配就称为近亲婚配 (consanguineous marriage)。,有亲缘关系的配偶，从他们共同的祖先得到同一基因，又将该基因同时传递给他们子女而使之成为纯合子的概率称为近婚系数(inbreeding coe
28、fficient, F)。,有亲缘关系的两个人携带相同基因的概率，称之为亲缘系数(coefficient of relationship)。,How many alleles do you have in common with.,Your dad / your kids ? Your sister ? Your half brother ? Your niece ? Your first cousin ? How similar are you ?,C,D,E,F,How many alleles do brother and sister share?,D,A,E,D,E,B,1/2,1/
29、2,1/2,1/2,1/2 x 1/2 = 1/4 = fraction of alleles D & E share from dad,1/2 x 1/2 = 1/4 = fraction of alleles D & E share from mom,1/4 + 1/4 = 1/2= fraction of alleles D & E share,C,D,E,F,D,G,A,E,H,D,G,E,H,B,1/2,1/2,1/2,1/2,1/2,1/2,1/2,1/2,1/2 x 1/2 x 1/2 x 1/2 = 1/16 = fraction of alleles G & H share
30、from common grandfather,1/2 x 1/2 x 1/2 x 1/2 = 1/16 = fraction of alleles G & H share from common grandmother,1/16 + 1/16 = 1/8 = fraction of alleles G & H share,How many alleles do you have in common with.,Your dad / your kids ? 1/2 Your sister ? 1/2 Your half brother ? 1/4 Your niece ? / Your unc
31、le ? 1/4 Your first cousin ? 1/8,近亲系数的计算 1. 常染色体基因,2. X连锁基因,群体平均近婚系数,对一个群体而言，用平均近婚系数（average inbreeding coefficient, a）来衡量群体近交的程度。,Example：有一群体共100人，其中5人来自表兄妹婚配（F=1/16），7人来自二级表兄妹婚配（F=1/64），其余88人父母无亲缘关系（F=0）。这一群体的平均近婚系数是：,1 16,a =,5,+,7 ,1 64,100,= 0. 0042,近亲婚配的危害,隐性纯合子患者的概率 = Fq + (1 F)q2 = q2 + Fpq
32、。 因此，群体中隐性致病基因的频率愈低，近亲婚配的危害也愈小。 隐性纯合的相对风险（）= (q2 + Fpq)/ q2 = 1 + Fp/q。因此，近亲婚配导致隐性纯合的相对风险总是大于或者等于随机婚配，F值愈大和q值愈低，近亲导致隐性纯合的相对风险愈高。,OUTLINE,What is Population Genetics? Genetic Constitutes of a Population - Gene & Genotype Frequencies Hardy Weinberg Equilibrium Factors that Alter Gene Frequencies Consanguineous Marriage and its Impact on Genetic Quality of a Population,See You then !,
