Kun Tang

A New Approach for Using Genome Scans to Detect Recent Positive Selection in the Human Genome

Genome-wide scanning for signals of recent positive selection is essential for a comprehensive and systematic understanding of human adaptation. Here, we present a genomic survey of recent local selective sweeps, especially aimed at those nearly or recently completed. A novel approach was developed for such signals, based on contrasting the extended haplotype homozygosity (EHH) profiles between populations. We applied this method to the genome single nucleotide polymorphism (SNP) data of both the International HapMap Project and Perlegen Sciences, and detected widespread signals of recent local selection across the genome, consisting of both complete and partial sweeps. A challenging problem of genomic scans of recent positive selection is to clearly distinguish selection from neutral effects, given the high sensitivity of the test statistics to departures from neutral demographic assumptions and the lack of a single, accurate neutral model of human history. We therefore developed a new procedure that is robust across a wide range of demographic and ascertainment models, one that indicates that certain portions of the genome clearly depart from neutrality. Simulations of positive selection showed that our tests have high power towards strong selection sweeps that have undergone fixation. Gene ontology analysis of the candidate regions revealed several new functional groups that might help explain some important interpopulation differences in phenotypic traits.

Distinct haplotype profiles and strong linkage disequilibrium at the MDR1 multidrug transporter gene locus in three ethnic Asian populations.

The MDR1 multidrug transporter plays a key role in determining drug bioavailability, and differences in drug response exist amongst different ethnic groups. Numerous studies have identified an association between the MDR1 single nucleotide polymorphism (SNP) exon 26 3435C>T and differences in MDR1 function. We performed a haplotype analysis of the MDR1 gene in three major ethnic groups (Chinese, Malays and Indians) by examining 10 intragenic SNPs. Four were polymorphic in all three ethnic groups: one occurring in the non-coding region and three occurring in coding exons. All three coding SNPs (exon 12 1236C>T, exon 21 2677G>T/A and exon 26 3435C>T) were present in high frequency in each ethnic group, and the derived haplotype profiles exhibited distinct differences between the groups. Fewer haplotypes were observed in the Malays (n = 6) compared to the Chinese (n = 10) and Indians (n = 9). Three major haplotypes (> 10% frequency) were observed in the Malays and Chinese; of these, two were observed in the Indians. Strong linkage disequilibrium (LD) was detected between the three SNPs in all three ethnic groups. The strongest LD was present in the Chinese, followed by Indians and Malays, with the corresponding LD blocks estimated to be approximately 80 kb, 60 kb and 40 kb, respectively. These data strongly support the hypothesis that strong LD between the neutral SNP exon 26 3435C>T and a nearby unobserved causal SNP underlies the observed associations between the neutral SNP and MDR1 functional differences. Furthermore, strong LD between exon 26 3435T and different unobserved causal SNPs in different study populations may provide a plausible explanation for conflicting reports associating the same exon 26 3435T allele with different MDR1 functional changes.

Identifying genes underlying skin pigmentation differences among human populations

Skin pigmentation is a human phenotype that varies greatly among human populations and it has long been speculated that this variation is adaptive. We therefore expect the genes that contribute to these large differences in phenotype to show large allele frequency differences among populations and to possibly harbor signatures of positive selection. To identify the loci that likely contribute to among-population human skin pigmentation differences, we measured allele frequency differentiation among Europeans, Chinese and Africans for 24 human pigmentation genes from 2 publicly available, large scale SNP data sets. Several skin pigmentation genes show unusually large allele frequency differences among these populations. To determine whether these allele frequency differences might be due to selection, we employed a within-population test based on long-range haplotype structure and identified several outliers that have not been previously identified as putatively adaptive. Most notably, we identify the DCT gene as a candidate for recent positive selection in the Chinese. Moreover, our analyses suggest that it is likely that different genes are responsible for the lighter skin pigmentation found in different non-African populations.

MDR1, the blood–brain barrier transporter, is associated with Parkinson’s disease in ethnic Chinese

Parkinson’s disease is the second most common neurodegenerative disease after Alzheimer’s disease. It is characterised by bradykinesia, rigidity, resting tremor, and postural instability.1 It is a genetically heterogeneous disorder. Pathogenic mutations in several genes—including α-synuclein , Parkin , UCH-L1 (ubiquitin-C terminal hydrolase-L1) and DJ -1—have previously been identified in rare monogenic forms of this disease showing autosomal dominant, autosomal recessive, or maternal transmission, with or without genetic anticipation.2,3 The more common, sporadic form of Parkinson’s disease appears to result from an interaction between genetic and environmental factors.4 Polymorphisms in several genes, including those implicated in familial forms of the disease such as α-synuclein 5 and Parkin ,6,7 are also reported to be associated with the sporadic form.8nnGenetic susceptibility to sporadic Parkinson’s disease was also found to be modulated by genes involved in xenobiotic management. A meta-analysis of 84 association studies of 14 genes showed that polymorphisms in four genes are significantly associated with the disease.9 These genes are either responsible for xenobiotic metabolism, such as NAT 210,11 and GST T1,12 or may interact with environmental agents, such as monoamine oxidase ( MAO B).13 Poor metaboliser alleles of the cytochrome P450 xenobiotic metabolism enzyme, CYP2D6, may also be associated with increased risk of Parkinson’s disease.14–20 Furthermore, there may be sex effects in the association of CYP 2D6 mutant alleles with Parkinson’s disease.21nnThese genetic association studies corroborate epidemiological studies, which have long suggested that Parkinson’s disease is associated with exposure to certain environmental xenobiotics. Although most of the specific agents remain to be identified, rural living, well water consumption, industrialisation, and herbicide/pesticide exposure have been implicated as potential risk factors.1,22,23nnAnother category of genes that may influence susceptibility to Parkinson’s disease is the …

Identification and Analysis of Genomic Regions with Large Between-Population Differentiation in Humans

The primary aim of genetic association and linkage studies is to identify genetic variants that contribute to phenotypic variation within human populations. Since the overwhelming majority of human genetic variation is found within populations, these methods are expected to be effective and can likely be extrapolated from one human population to another. However, they may lack power in detecting the genetic variants that contribute to phenotypes that differ greatly between human populations. Phenotypes that show large differences between populations are expected to be associated with genomic regions exhibiting large allele frequency differences between populations. Thus, from genome‐wide polymorphism data genomic regions with large allele frequency differences between populations can be identified, and evaluated as candidates for large between‐population phenotypic differences. Here we use allele frequency data from ∼1.5 million SNPs from three human populations, and present an algorithm that identifies genomic regions containing SNPs with extreme Fst. We demonstrate that our candidate regions have reduced heterozygosity in Europeans and Chinese relative to African‐Americans, and are likely enriched with genes that have experienced positive natural selection. We identify genes that are likely responsible for phenotypes known to differ dramatically between human populations and present several candidates worthy of future investigation. Our list of high Fst genomic regions is a first step in identifying the genetic variants that contribute to large phenotypic differences between populations, many of which have likely experienced positive natural selection. Our approach based on between population differences can compliment traditional within population linkage and association studies to uncover novel genotype‐phenotype relationships.

Analysis of MDR1 haplotypes in Parkinson's disease in a white population

The MDR1 multidrug transporter is important in regulating environmental xenobiotics and hence may play a causative role in Parkinsons disease (PD). MDR1 haplotype comprising 2677 G > T/A and 3435 C > T may be protective against PD. Using a case control methodology, we investigated the association of MDR1 haplotypes (single nucleotide polymorphisms (SNPs) 2677 G > T/A and 3435 C > T) in a Polish PD population. Seven SNPs, extending from the promoter to exon 28 of the MDR1 gene in 158 PD patients and 139 healthy controls were evaluated. Specifically we examined the association of haplotypes containing SNPs 2677 G > T/A and 3435 C > T and risk of PD. The multivariate logistic regression model was used to evaluate the effects of the covariates on the phenotypes. Haplotypes frequencies were estimated using the Expectation-Maximization algorithm. The frequency of each individual SNPs; -41 A > G (intron -1), -145 C > G (exon 1), -129 T > C (exon 1), 1236 T > C (exon 12), 2677 G > T/A (exon 21), 3435 C > T (exon 26), and 4036 A > G (exon 28) did not differ between PD and controls. However, there was a trend towards significance in PD patients having the haplotype 2677G-3435C (p < 0.09, chi-square 2.85, odds ratio 0.25, 95% CI 0.06-1.08). Haplotype constructs of the other loci did not differ significantly between the two groups. There was a weak protective effect of the haplotype 2677G-3435C in our white population. However, the MDR1 haplotypes did not generally modulate the risk of PD.

Positive selection on gene expression in the human brain

Document S1. Supplemental Experimental ProceduresxDownload (.1 MB ) Document S1. Supplemental Experimental Procedures

Simultaneous Genotyping of Seven Single-Nucleotide Polymorphisms in the MDR1 Gene by Single-Tube Multiplex Minisequencing

Responses to different drugs can vary widely among different individuals as a result of genetic variations in drug-metabolizing enzymes, transporters, receptors, and/or other cofactors. The multidrug resistance 1 (MDR1) transporter, a well-characterized member of the ATP-binding cassette superfamily, was shown to efflux a wide variety of structurally and functionally unrelated drugs, including anticancer, antiarrhythmic, antidepressant, antipsychotic, and antiviral agents. The pharmacogenetics of the MDR1 multidrug transporter have recently received much scientific attention. Several single-nucleotide polymorphisms (SNPs) have been identified in the MDR1 gene; some occur only in specific ethnic groups, whereas others occur in all ethnic groups but at significantly different allele frequencies among the different races [see Ref. (1) and references therein]. Nonetheless, the functional significance of these SNPs remains unclear. Various functional associations, some paradoxical, have been observed between the synonymous SNP (exon 26 3435C→T) and MDR1 protein expression and plasma drug concentrations (2)(3)(4)(5), drug-induced side effects (6), and drug response (7). The SNP exon 26 3435T allele has been associated with lower MDR1 expression in the duodenum (2), leukocytes (5), and placental tissues (8), leading to lower rhodamine efflux (5) and increased plasma digoxin concentrations (2). In addition, early-onset Parkinson patients have higher frequency of the SNP exon 26 3435T allele compared with late-onset patients or unaffected controls (9). However, although this same allele has been associated with lower MDR1 expression in peripheral blood mononuclear cells and better response to HIV-1 drugs, it has also been associated with lower plasma concentrations of nelfinavir (7). Additionally, the SNP exon 26 3435T allele has been associated with an increased risk of nortriptyline-induced postural hypertension, although blood concentrations of nortriptyline in these individuals were not significantly different from those in individuals carrying the C allele (6). Furthermore, no association has been demonstrated between the …

FMR1 CGG repeat patterns and flanking haplotypes in three Asian populations and their relationship with repeat instability.

Hyper‐expansion of a CGG repeat in the 5′ untranslated region of the FMR1 gene followed by methylation and silencing is the predominant cause of Fragile X syndrome, the most common inherited mental retardation disorder. Most detailed studies of the FMR1 gene have focused on Caucasian populations and patients. We performed a detailed haplotype and linkage disequilibrium analysis of the FMR1 gene in a total of 454 unselected normal X chromosomes from three Asian populations, Chinese, Malay and Indian. Compared to Caucasians and African Americans, the diversity of normal FMR1 CGG repeat lengths, patterns and flanking haplotypes were lower in Asians. Strong linkage disequilibrium was observed between the CGG repeat and flanking FMR1 markers in all three Asian populations, with strong association between specific CGG repeat alleles and flanking marker alleles observed only in the Chinese and Malays. A test for randomness of distribution between FRAXA CGG repeat patterns and flanking FMR1 marker haplotypes also revealed a highly significant non‐random distribution between CGG repeat patterns and flanking haplotypes in all three ethnic groups (P < 0.001). Extending previous findings in Caucasians and African Americans we present a novel statistical approach, using data from unselected population samples alone, to show an association between absence of at least one AGG interruption in any position (5′, 3′, or middle) and increased CGG repeat instability.

Strong linkage disequilibrium at the nucleotide analogue transporter ABCC5 gene locus.

The ABCC5 transporter is a ubiquitously expressed ATP-dependent efflux pump that exports nucleotide analogues, including thiopurine anticancer drugs and antiviral drugs. Polymorphisms within this gene may be associated with differences in response to these drugs between different individuals. Haplotype mapping may facilitate the identification of causal genetic variations in association studies. Here, we report the characterization of the haplotype and linkage disequilibrium (LD) profiles across the entire 100u2009kb of the ABCC5 gene in five ethnically unique populations. Of 24 single nucleotide polymorphisms (SNPs) examined, 16 were observed to occur at high frequency in all five populations and were used for further haplotype and LD analyses. The ABCC5 gene was found to be in strong LD in all populations with half-length LD (LD0.5) estimated to be between 106 and 293u2009kb long and useful LD extending beyond 100u2009kb. Low haplotype diversity was observed in the four non-African populations, where the total number of observed haplotypes constituted less than 22% of the predicted number of haplotypes in a simulated population that has undergone maximum recombination. Four and six tagging SNPs, which could account for approximately 90% of observed haplotypes, were identified in the non-African and African-American populations, respectively.