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1、人类群体遗传学 基本原理和分析方法,中科院-马普学会计算生物学伙伴研究所,中国科学院上海生命科学研究院研究生课程 人类群体遗传学,徐书华 金 力,20072008学年第二学期人类群体遗传学分析方法课程表 上课时间：每周四上午10:00-11:50 上课地点：中科大厦4楼403室第7教室,第五讲,单倍型估计及连锁不平衡分析,第五讲,基本概念 连锁不平衡原理及其统计量 影响连锁不平衡的因素 连锁不平衡在基因定位研究中的应用,基本概念,遗传多态性（Genetic polymorphism） 指在一个群体中，同时存在的两种或两种以上的变异类型，每种类型的频率比较高，一般认为每种变异型超过1即可定为多态
2、现象，不足1的称为罕见变异型，或者称为突变（mutation）。 人类存在多种遗传多态现象（多态性），主要有染色体多态性、酶和蛋白质多态性、抗原多态性的DNA多态性五类。,单核苷酸多态性,单核苷酸多态性(single nucleotide polymorphism，SNP，读作 “snip” ),主要是指在基因组水平上由单个核苷酸的变异所引起的DNA序列多态性。它是人类可遗传的变异中最常见的一种。占所有已知多态性的90%以上。SNP在人类基因组中广泛存在，平均每300600个碱基对中就有1个，估计其总数可达1000万个甚至更多。 SNP所表现的多态性只涉及到单个碱基的变异，这种变异可由单个碱基
3、的转换(transition)或颠换(transversion)所引起，也可由碱基的插入或缺失所致。但通常所说的SNP并不包括后两种情况。 理论上讲，SNP既可能是二等位多态性，也可能是3个或4个等位多态性，但实际上，后两者非常少见，几乎可以忽略。因此，通常所说的SNP都是二等位多态性的（biallelic）。,genotype,相邻位点的等位基因在同一条染色体上的排列方式,From genotype to haplotype,genotype,haplotype,phased data,unphased data,Reconstruct haplotype from genotype,CLA
4、RKS algorithm Parsimony-based method E-M algorithm Likelihood-based method PHASE algorithm Bayesian method,Reconstruct haplotype at individual level,00100111010101000001111101011011111111110100100001010101110110000111011000001101110011111000010 0010111111101011111010001010010000000010000110000011010
5、0011100110000000011111100110001000100000 00101111010101000001111101011010111111110101001001000000000101000000000000001100110001000100000 11010111010101000001111101011010111111110100111100011111110101000001100011111100110001000100000 0010011101010100000111110101101111111111010010000101010111011000011
6、1010000001000001100010011011 11010011010101000001111101011011111111110100000011000000000000010000000100000100110001000100000 00101111010101000001111101011010111111110100101001000000000101000000000000001000001100010011011 1101000000000000000000000000000000000000100000001100000000000001000000010000010
7、0110001000100000 00000000000000000000000000000000000000001010000011000000000000010000000100000100110001000100000 11010111010101000001111101011010111111110100101001000000000101000000000000001000001100010011011 0000000000000000000000000000000000000000100010000011010001110010100000000000100000110001001
8、1011 00101111111010111110100010100100000000100001100000110100011100110000000000000100110001000100000 00000000000000000000000000000000000000001010000011000000000000010000001100000100110001000100000 11010100000000000000000000000000000000001000000011000000000000010000000100000101110011111000010 0000000
9、0000000000000000000000000000000001010111100011111110101010000000100000100110001000100000 00000000000000000000000000000000000000001010000011000000000000010000000100000100110001000100000 00101111111010111110100010100100000000100001100000110100011100110000000100000100110001000100000 1101011111101011111
10、0100010100100000000100001101001000000000100000001100000000110010011010000110 00000000000000000000000000000000000000001010111100011111110101000011100000001101110011111000010 00101111111010111110100010100100000000100001000011000000000000010000000100000101110011111000010 0010111111101011111010001010010
11、0000000100001100000110100011100101000000000001000001100010011011 11010111111010111110100010100100000000100001100000110100011100101000000000001000001100010011011 00000000000000000000000000000000000000001000000011000000000000010000000100000100110001000100000 1101011111101011111010001010010000000010000
12、1100000110100011100101000000000001000001100010011011 00000000000000000000000000000000000000001010111100011111110101010000000100000100110001000100000 00000000000000000000000000000000000000001010100000110100011100101000000000001000001100010011011 0010111111101011111010001010010000000010000111000001111
13、1110101000000000011111110010011010001010 11010111010101000001111101011010111111110100101001000000000101000000000000001000001100010011011,软件演示,PHASE & fastPHASE,PHASE input file format,Position and Locus type,Genotype coding,Example of input file format,PHASE input file format,40 7 P 13549576 1362167
14、6 13706156 13708283 13958290 14224204 14312716 SSSSSSS YRI-1 TGTTCTT CCCCCCC YRI-2 TCCCCTT TCCCCTT YRI-3 TGCTCTT CCCTCCT YRI-4 TGTCCTT CCCCCCT YRI-5 TGCTCTT CCCCCCC YRI-6 TCTCCTT TCCCCCT,Alterative format,- f option -n option,Options affecting run times and accuracy,-X option,Running PHASE multiple
15、times,-x option,Running several data sets from the same input file,-D option,Linkage Disequilibrium (LD),LD is the non-random association of alleles at adjacent loci. When a particular allele at one locus is found together on the same chromosome with a specific allele at a second locus more often th
16、an expected if the loci were segregating independently in a population the loci are in disequilibrium.,连锁不平衡,Linkage Disequilibrium (LD) 是相邻位点之间的非随机关联，当一个位点上的某一等位基因与另一位点上的等位基因共同出现的概率大于随机组合的假设，则这两个位点之间存在连锁不平衡。,Commonly used LD measurements,(Lewontin, 1964),(Hill & Weir, 1994),Independence test（p-value）,2x2 table test,Fisher exact test,Population recombination rate (4Ner),4Ner: population recombination parameter. Alternatively denoted by
