The International HapMap Consortium. The International HapMap Project (Co-PI of Hong Kong Centre which responsible for 2.5% of genome)

Recombination rate and linkage disequilibrium, the latter a function of population genomic processes, are the critical parameters for mapping by linkage and association, and their patterns in Caenorhabditis elegans are poorly understood. We performed high-density SNP genotyping on a large panel of recombinant inbred advanced intercross lines (RIAILs) of C. elegans to characterize the landscape of recombination and, on a panel of wild strains, to characterize population genomic patterns. We confirmed that C. elegans autosomes exhibit discrete domains of nearly constant recombination rate, and we show, for the first time, that the pattern holds for the X chromosome as well. The terminal domains of each chromosome, spanning about 7% of the genome, exhibit effectively no recombination. The RIAILs exhibit a 5.3-fold expansion of the genetic map. With median marker spacing of 61 kb, they are a powerful resource for mapping quantitative trait loci in C. elegans. Among 125 wild isolates, we identified only 41 distinct haplotypes. The patterns of genotypic similarity suggest that some presumed wild strains are laboratory contaminants. The Hawaiian strain, CB4856, exhibits genetic isolation from the remainder of the global population, whose members exhibit ample evidence of intercrossing and recombining. The population effective recombination rate, estimated from the pattern of linkage disequilibrium, is correlated with the estimated meiotic recombination rate, but its magnitude implies that the effective rate of outcrossing is extremely low, corroborating reports of selection against recombinant genotypes. Despite the low population, effective recombination rate and extensive linkage disequilibrium among chromosomes, which are techniques that account for background levels of genomic similarity, permit association mapping in wild C. elegans strains.

https://escholarship.org/content/qt1n7317b5/qt1n7317b5.pdf?t=qaelyy

Recombinational landscape and population genomics of Caenorhabditis elegans.

Long tracts of consecutive homozygous single nucleotide polymorphisms (SNPs) can arise in the genome through a number of mechanisms. These include inbreeding in which an individual inherits chromosomal segments that are identical by descent from each parent. However, recombination and other processes break up chromosomal segments over generations. The longest tracts are therefore to be expected in populations with an appreciable degree of inbreeding. We examined the length, number and distribution of long tracts of homozygosity in the apparently outbred HapMap populations. We observed 1393 tracts exceeding 1 Mb in length among the 209 unrelated HapMap individuals. The longest was an uninterrupted run of 3922 homozygous SNPs spanning 17.9 Mb in a Japanese individual. We find that homozygous tracts are significantly more common in regions with high linkage disequilibrium and low recombination, and the location of tracts is similar across all populations. The Yoruba sample has the fewest long tracts per individual, consistent with a larger number of generations (and hence amount of recombination) since the founding of that population. Our results suggest that multiple-megabase-scale ancestral haplotypes persist in outbred human populations in broad genomic regions which have lower than average recombination rates. We observed three outlying individuals who have exceptionally long and numerous homozygous tracts that are not associated with recombination suppressed areas of the genome. We consider that this reflects a high level of relatedness in their ancestry which is too recent to have been influenced by the local recombination intensity. Possible alternative mechanisms and the implications of long homozygous tracts in the genome are discussed.

/pdf/extended-tracts-of-homozygosity-in-outbred-human-populations-3vi5n6ovvr.pdf

Extended tracts of homozygosity in outbred human populations

Genetic susceptibility to multiple sclerosis is associated with genes of the major histocompatibility complex (MHC), particularly HLA-DRB1 and HLA-DQB1 (ref. 1). Both locus and allelic heterogeneity have been reported in this genomic region. To clarify whether HLA-DRB1 itself, nearby genes in the region encoding the MHC or combinations of these loci underlie susceptibility to multiple sclerosis, we genotyped 1,185 Canadian and Finnish families with multiple sclerosis (n = 4,203 individuals) with a high-density SNP panel spanning the genes encoding the MHC and flanking genomic regions. Strong associations in Canadian and Finnish samples were observed with blocks in the HLA class II genomic region (P < 4.9 x 10(-13) and P < 2.0 x 10(-16), respectively), but the strongest association was with HLA-DRB1 (P < 4.4 x 10(-17)). Conditioning on either HLA-DRB1 or the most significant HLA class II haplotype block found no additional block or SNP association independent of the HLA class II genomic region. This study therefore indicates that MHC-associated susceptibility to multiple sclerosis is determined by HLA class II alleles, their interactions and closely neighboring variants.

A predominant role for the HLA class II region in the association of the MHC region with multiple sclerosis.

The genome-wide distribution of linkage disequilibrium (LD) determines the strategy for selecting markers for association studies, but it varies between populations. We assayed LD in large samples (200 individuals) from each of 11 well-described population isolates and an outbred European-derived sample, using SNP markers spaced across chromosome 22. Most isolates show substantially higher levels of LD than the outbred sample and many fewer regions of very low LD (termed 'holes'). Young isolates known to have had relatively few founders show particularly extensive LD with very few holes; these populations offer substantial advantages for genome-wide association mapping.

Magnitude and distribution of linkage disequilibrium in population isolates and implications for genome-wide association studies

The extent and patterns of linkage disequilibrium (LD) determine the feasibility of association studies to map genes that underlie complex traits. Here we present a comparison of the patterns of LD across four major human populations (African-American, Caucasian, Chinese, and Japanese) with a high-resolution single-nucleotide polymorphism (SNP) map covering almost the entire length of chromosomes 6, 21, and 22. We constructed metric LD maps formulated such that the units measure the extent of useful LD for association mapping. LD reaches almost twice as far in chromosome 6 as in chromosomes 21 or 22, in agreement with their differences in recombination rates. By all measures used, out-of-Africa populations showed over a third more LD than African-Americans, highlighting the role of the population's demography in shaping the patterns of LD. Despite those differences, the long-range contour of the LD maps is remarkably similar across the four populations, presumably reflecting common localization of recombination hot spots. Our results have practical implications for the rational design and selection of SNPs for disease association studies.

/pdf/the-linkage-disequilibrium-maps-of-three-human-chromosomes-4jo6y937jp.pdf

The linkage disequilibrium maps of three human chromosomes across four populations reflect their demographic history and a common underlying recombination pattern

Methods and systems for ordering assays which detect SNPs or gene expression are provided. The methods use PCR and RT-PCR procedures. Collections of stock assays are assembled using pre- and post-manufacturing quality control procedures and made available to consumers via the Internet. In addition, custom assays are prepared upon order from the consumer and these assays are also prepared using pre- and post-manufacturing quality control procedures. The assays are then delivered to the consumer.

Methods for placing, accepting, and filling orders for products and services

data analysis software, DataAssist™ software, has been developed for quick analysis and interactive visualization of TaqMan® real-time PCR data. It uses the comparative C T method (also known as the 2-ΔΔCt method) [1] to calculate relative quantities (RQ) of gene expression for sample comparison. The software uses a refined Grubbs' outlier test to remove outlier among technical replicates, provides a metric to measure control gene stability based on the geNorm algorithm [2] to assist with endogenous control selection, and allows using single or multiple control genes for data normalization. The software provides a function-rich graphic user interface (GUI), many content-rich tables and scalable graphics charts for easy, interactive, and rapid high-throughput data analysis and visualization.

/pdf/dataassist-data-analysis-software-for-taqman-real-time-pcr-1bmzdkd32g.pdf

Xiaoqing You

Papers

The linkage disequilibrium maps of three human chromosomes across four populations reflect their demographic history and a common underlying recombination pattern

Methods for placing, accepting, and filling orders for products and services

DataAssist™ - Data Analysis Software for TaqMan® Real-Time PCR Data

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