The patterns of natural variation in human genes

被引:80
作者
Crawford, DC [1 ]
Akey, DT [1 ]
Nickerson, DA [1 ]
机构
[1] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA
关键词
SNPs; haplotypes; diversity; association; linkage disequilibrium; Environmental Genome Project; SeattleSNPs Program for Genomic Applications;
D O I
10.1146/annurev.genom.6.080604.162309
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Currently, more than 10 million DNA sequence variations have been uncovered in the human genome. The most detailed variation discovery efforts have focused on candidate genes involved in cardiovascular disease or in susceptibilities associated with exposure to environmental agents. Here we provide an overview of natural genetic variation from the literature and in 510 human candidate genes resequenced for variation discovery. The average human gene contains 126 biallelic polymorphisms, 46 of which are common (>= 5% minor allele frequency) and 5 of which are found in coding regions. Using this complete picture of genetic diversity, we explore conservation, signatures of selection, and historical recombination to mine information useful for candidate gene association studies. In general, we find that the patterns of human gene variation suggest that no one approach will be appropriate for genetic association studies across all genes. Therefore, many different approaches may be required to identify the elusive genotypes associated with common human phenotypes.
引用
收藏
页码:287 / 312
页数:32
相关论文
共 118 条
  • [71] Blocks of limited haplotype diversity revealed by high-resolution scanning of human chromosome 21
    Patil, N
    Berno, AJ
    Hinds, DA
    Barrett, WA
    Doshi, JM
    Hacker, CR
    Kautzer, CR
    Lee, DH
    Marjoribanks, C
    McDonough, DP
    Nguyen, BTN
    Norris, MC
    Sheehan, JB
    Shen, NP
    Stern, D
    Stokowski, RP
    Thomas, DJ
    Trulson, MO
    Vyas, KR
    Frazer, KA
    Fodor, SPA
    Cox, DR
    [J]. SCIENCE, 2001, 294 (5547) : 1719 - 1723
  • [72] Genomic strategies to identify mammalian regulatory sequences
    Pennacchio, LA
    Rubin, EM
    [J]. NATURE REVIEWS GENETICS, 2001, 2 (02) : 100 - 109
  • [73] The methionine 196 arginine polymorphism in exon 6 of the TNF receptor 2 gene (TNFRSF1B) is associated with the polycystic ovary syndrome and hyperandrogenism
    Peral, B
    San Millán, JL
    Castello, R
    Moghetti, P
    Escobar-Morreale, HF
    [J]. JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2002, 87 (08) : 3977 - 3983
  • [74] Chromosome-wide distribution of haplotype blocks and the role of recombination hot spots
    Phillips, MS
    Lawrence, R
    Sachidanandam, R
    Morris, AP
    Balding, DJ
    Donaldson, MA
    Studebaker, JF
    Ankener, WM
    Alfisi, SV
    Kuo, FS
    Camisa, AL
    Pazorov, V
    Scott, KE
    Carey, BJ
    Faith, J
    Katari, G
    Bhatti, HA
    Cyr, JM
    Derohannessian, V
    Elosua, C
    Forman, AM
    Grecco, NM
    Hock, CR
    Kuebler, JM
    Lathrop, JA
    Mockler, MA
    Nachtman, EP
    Restine, SL
    Varde, SA
    Hozza, MJ
    Gelfand, CA
    Broxholme, J
    Abecasis, GR
    Boyce-Jacino, MT
    Cardon, LR
    [J]. NATURE GENETICS, 2003, 33 (03) : 382 - 387
  • [75] Are rare variants responsible for susceptibility to complex diseases?
    Pritchard, JK
    [J]. AMERICAN JOURNAL OF HUMAN GENETICS, 2001, 69 (01) : 124 - 137
  • [76] The allelic architecture of human disease genes: common disease - common variant ... or not?
    Pritchard, JK
    Cox, NJ
    [J]. HUMAN MOLECULAR GENETICS, 2002, 11 (20) : 2417 - 2423
  • [77] Linkage disequilibrium in humans: Models and data
    Pritchard, JK
    Przeworski, M
    [J]. AMERICAN JOURNAL OF HUMAN GENETICS, 2001, 69 (01) : 1 - 14
  • [78] A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans
    Prokunina, L
    Castillejo-López, C
    Öberg, F
    Gunnarsson, I
    Berg, L
    Magnusson, V
    Brookes, AJ
    Tentler, D
    Kristjansdóttir, H
    Gröndal, G
    Bolstad, AI
    Svenungsson, E
    Lundberg, I
    Sturfelt, G
    Jönssen, A
    Truedsson, L
    Lima, G
    Alcocer-Varela, J
    Jonsson, R
    Gyllensten, UB
    Harley, JB
    Alarcón-Segovia, D
    Steinsson, K
    Alarcón-Riquelme, ME
    [J]. NATURE GENETICS, 2002, 32 (04) : 666 - 669
  • [79] Human non-synonymous SNPs: server and survey
    Ramensky, V
    Bork, P
    Sunyaev, S
    [J]. NUCLEIC ACIDS RESEARCH, 2002, 30 (17) : 3894 - 3900
  • [80] Linkage disequilibrium in the human genome
    Reich, DE
    Cargill, M
    Bolk, S
    Ireland, J
    Sabeti, PC
    Richter, DJ
    Lavery, T
    Kouyoumjian, R
    Farhadian, SF
    Ward, R
    Lander, ES
    [J]. NATURE, 2001, 411 (6834) : 199 - 204