How Array Design affects SNP Ascertainment Bias

Geibel, Johannes; Reimer, Christian; Weigend, Steffen; Weigend, Annett; Pook, Torsten; Simianer, Henner

doi:10.1101/833541

Cited by 5 publications

(7 citation statements)

References 63 publications

(55 reference statements)

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“…A limitation of the other two Bos genus (YAK and BLI) datasets are the genomic datasets, in which genotyping platforms developed for cattle (a closely related Bovidae species) were used. This might have resulted in ascertainment bias ( Lachance and Tishkoff, 2013 ; Malomane et al, 2018 ; Geibel et al, 2019 ) in the results of YAK and BLI, as discussed later. Genotypic quality control (QC) was implemented for all breeds together.…”

Section: Methodsmentioning

confidence: 99%

Genetic Diversity and Signatures of Selection for Thermal Stress in Cattle and Other Two Bos Species Adapted to Divergent Climatic Conditions

et al. 2021

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Understanding the biological mechanisms of climatic adaptation is of paramount importance for the optimization of breeding programs and conservation of genetic resources. The aim of this study was to investigate genetic diversity and unravel genomic regions potentially under selection for heat and/or cold tolerance in thirty-two worldwide cattle breeds, with a focus on Chinese local cattle breeds adapted to divergent climatic conditions, Datong yak (Bos grunniens; YAK), and Bali (Bos javanicus) based on dense SNP data. In general, moderate genetic diversity levels were observed in most cattle populations. The proportion of polymorphic SNP ranged from 0.197 (YAK) to 0.992 (Mongolian cattle). Observed and expected heterozygosity ranged from 0.023 (YAK) to 0.366 (Sanhe cattle; SH), and from 0.021 (YAK) to 0.358 (SH), respectively. The overall average inbreeding (±SD) was: 0.118 ± 0.028, 0.228 ± 0.059, 0.194 ± 0.041, and 0.021 ± 0.004 based on the observed versus expected number of homozygous genotypes, excess of homozygosity, correlation between uniting gametes, and runs of homozygosity (ROH), respectively. Signatures of selection based on multiple scenarios and methods (FST, HapFLK, and ROH) revealed important genomic regions and candidate genes. The candidate genes identified are related to various biological processes and pathways such as heat-shock proteins, oxygen transport, anatomical traits, mitochondrial DNA maintenance, metabolic activity, feed intake, carcass conformation, fertility, and reproduction. This highlights the large number of biological processes involved in thermal tolerance and thus, the polygenic nature of climatic resilience. A comprehensive description of genetic diversity measures in Chinese cattle and YAK was carried out and compared to 24 worldwide cattle breeds to avoid potential biases. Numerous genomic regions under positive selection were detected using three signature of selection methods and candidate genes potentially under positive selection were identified. Enriched function analyses pinpointed important biological pathways, molecular function and cellular components, which contribute to a better understanding of the biological mechanisms underlying thermal tolerance in cattle. Based on the large number of genomic regions identified, thermal tolerance has a complex polygenic inheritance nature, which was expected considering the various mechanisms involved in thermal stress response.

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Section: Methodsmentioning

confidence: 99%

Genetic Diversity and Signatures of Selection for Thermal Stress in Cattle and Other Two Bos Species Adapted to Divergent Climatic Conditions

et al. 2021

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“…This results in a shift of the allele frequency spectrum towards mean allele frequencies and thereby an overestimation of heterozygosity compared to whole genome resequencing (WGS) data. As this overestimation is stronger for populations involved in the array design (discovery populations) than for those not involved [9], follow-up analyses can be biased. This effect is widely known as SNP Ascertainment Bias [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

How Imputation Can Mitigate Ascertainment Bias

Geibel

Reimer

Pook

et al. 2021

Preprint

Self Cite

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Background Population genetic studies based on genotyped single nucleotide polymorphisms (SNPs) are influenced by a non-random selection of the SNPs included in the used genotyping arrays. The resulting bias relative to whole genome sequencing (WGS) data is known as SNP ascertainment bias. Correction for this bias requires detailed knowledge of the array design process which is often not available in practice. This study intends to investigate an alternative approach to mitigate ascertainment bias of a large set of genotyped individuals by using information of a small set of sequenced individuals via imputation without the need for prior knowledge on the array design. Results The strategy was first tested by simulating additional ascertainment bias with a set of 1,566 chickens from 74 populations that were genotyped for the positions of the Affymetrix Axiom™ 580k Genome-Wide Chicken Array. Imputation accuracy was shown to be consistently higher for populations used for SNP discovery during the simulated array design process. Reference sets of at least one individual per population in the study set led to a strong correction of ascertainment bias for estimates of expected and observed heterozygosity, Wrights Fixation Index and Nei’s Standard Genetic Distance. In contrast, unbalanced reference sets introduced a new bias towards the reference populations. Finally, the array genotypes were imputed to WGS by utilization of reference sets of 74 individuals (one per population) to 98 individuals (additional commercial chickens) and compared with a mixture of individually and pooled sequenced populations. The imputation reduced the slope between heterozygosity estimates of array data and WGS data from 1.94 to 1.26 when using the smaller balanced reference panel and to 1.44 when using the larger but unbalanced reference panel. This generally supported the results from simulation but was less favorable, advocating for a larger reference panel when imputing to WGS. Conclusions The results highlight the potential of using imputation for mitigation of SNP ascertainment bias but also underline the need for unbiased reference sets.

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“…Generally, SNP chips (or genotyping array) data tends to underrepresent rare variants that are likely to be detected in sequence data like the one used in this study. Since the extent of LD ( r 2 ) depends on MAF, it is expected that there would be a little difference in the r 2 value obtained from both studies, partly due to SNP ascertainment bias on SNP chip data ( Lachance and Tishkoff, 2013 ; Geibel et al, 2019 ). This kind of bias was reduced in a recent study by Huang et al (2020) which had more Chinese breeds represented in the design of the SNP array used.…”

Section: Discussionmentioning

confidence: 99%

Haplotype Block Analysis Reveals Candidate Genes and QTLs for Meat Quality and Disease Resistance in Chinese Jiangquhai Pig Breed

Oyelami

Zhao

et al. 2020

Front. Genet.

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The Jiangquhai (JQ) pig breed is one of the most widely recognized pig populations in China due to its unique and dominant characteristics. In this study, we examined the extent of Linkage disequilibrium (LD) and haplotype block structure of the JQ pig breed, and scanned the blocks for possible genes underlying important QTLs that could either be responsible for some adaptive features in these pigs or might have undergone some selection pressure. We compared some of our results with other Chinese and Western pig breeds. The results show that the JQ breed had the highest total block length (349.73 Mb ≈ 15% of its genome), and the coverage rate of blocks in most of its chromosomes was larger than those of other breeds except for Sus scrofa chromosome 4 (SSC4), SSC6, SSC7, SSC8, SSC10, SSC12, SSC13, SSC14, SSC17, SSC18, and SSCX. Moreover, the JQ breed had more SNPs that were clustered into haplotype blocks than the other breeds examined in this study. Our shared and unique haplotype block analysis revealed that the Hongdenglong (HD) breed had the lowest percentage of shared haplotype blocks while the Shanzhu (SZ) breed had the highest. We found that the JQ breed had an average r 2 > 0.2 at SNPs distances 10–20 kb and concluded that about 120,000–240,000 SNPs would be needed for a successful GWAS in the breed. Finally, we detected a total of 88 genes harbored by selected haplotype blocks in the JQ breed, of which only 4 were significantly enriched ( p-value ≤ 0.05). These genes were significantly enriched in 2 GO terms ( p-value < 0.01), and 2 KEGG pathways ( p-value < 0.02). Most of these enriched genes were related to health. Also, most of the overlapping QTLs detected in the haplotype blocks were related to meat and carcass quality, as well as health, with a few of them relating to reproduction and production. These results provide insights into the genetic architecture of some adaptive and meat quality traits observed in the JQ pig breed and also revealed the pattern of LD in the genome of the pig. Our result provides significant guidance for improving the statistical power of GWAS and optimizing the conservation strategy for this JQ pig breed.

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How Array Design affects SNP Ascertainment Bias

Cited by 5 publications

References 63 publications

Genetic Diversity and Signatures of Selection for Thermal Stress in Cattle and Other Two Bos Species Adapted to Divergent Climatic Conditions

Genetic Diversity and Signatures of Selection for Thermal Stress in Cattle and Other Two Bos Species Adapted to Divergent Climatic Conditions

How Imputation Can Mitigate Ascertainment Bias

Haplotype Block Analysis Reveals Candidate Genes and QTLs for Meat Quality and Disease Resistance in Chinese Jiangquhai Pig Breed

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