Dataset Information

The performance of common SNP arrays in assigning African mitochondrial haplogroups.

ABSTRACT:

Background

Mitochondrial haplogroup assignment is an important tool for forensics and evolutionary genetics. African populations are known to display a high diversity of mitochondrial haplogroups. In this research we explored mitochondrial haplogroup assignment in African populations using commonly used genome-wide SNP arrays.

Results

We show that, from eight commonly used SNP arrays, two SNP arrays outperform the other arrays when it comes to the correct assignment of African mitochondrial haplogroups. One array enables the recognition of 81% of the African mitochondrial haplogroups from our compiled dataset of full mitochondrial sequences. Other SNP arrays were able to assign 4-62% of the African mitochondrial haplogroups present in our dataset. We also assessed the performance of available software for assigning mitochondrial haplogroups from SNP array data.

Conclusions

These results provide the first cross-checked quantification of mitochondrial haplogroup assignment performance from SNP array data. Mitochondrial haplogroup frequencies inferred from most common SNP arrays used for human population analysis should be considered with caution.

SUBMITTER: Lankheet I

PROVIDER: S-EPMC8532338 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Publications

The performance of common SNP arrays in assigning African mitochondrial haplogroups.

Lankheet Imke I Vicente Mário M Barbieri Chiara C Schlebusch Carina C

BMC genomic data 20211021 1

<h4>Background</h4>Mitochondrial haplogroup assignment is an important tool for forensics and evolutionary genetics. African populations are known to display a high diversity of mitochondrial haplogroups. In this research we explored mitochondrial haplogroup assignment in African populations using commonly used genome-wide SNP arrays.<h4>Results</h4>We show that, from eight commonly used SNP arrays, two SNP arrays outperform the other arrays when it comes to the correct assignment of African mit ...[more]

PMID: 34674637

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Project description:PurposeTo estimate the population frequencies of all common mitochondrial variants and ancestral haplogroups among 1,999 subjects recruited for the Primary Open-Angle African American Glaucoma Genetics (POAAGG) Study, including 1,217 primary open-angle glaucoma (POAG) cases and 782 controls, and to identify ancestral subpopulations and mitochondrial mutations as potential risk factors for POAG susceptibility.MethodsSubject classification by characteristic glaucomatous optic nerve findings and corresponding visual field defects, as defined by enrolling glaucoma specialists, stereo disc photography, phlebotomy, extraction of total DNA from peripheral blood or saliva, DNA quantification and normalization, PCR amplification of whole mitochondrial genomes, Ion Torrent deep semiconductor DNA sequencing on DNA pools ("Pool-seq"), Sanger sequencing of 3,479 individual mitochondrial DNAs, and bioinformatic analysis.ResultsThe distribution of common African haplogroups within the POAAGG study population was broadly similar to prior surveys of African Americans. However, the POAG case population was found to be enriched in L1c2 haplogroups, which are defined in part by missense mutations m.6150G>A (Val83Ile, odds ratio [OR] 1.8, p=0.01), m.6253C>T (Met117Thr, rs200165736, OR 1.6, p=0.04), and m.6480G>A (Val193Ile, rs199476128, OR 4.6, p=0.04) in the cytochrome c oxidase subunit 1 (MT-CO1) gene and by a variant, m.2220A>G (OR 2.0, p=0.01), in MT-RNR2, which encodes the mitochondrial ribosomal 16s RNA gene. L2 haplogroups were predicted to be overrepresented in the POAG case population by Pool-seq, and the difference was confirmed to be significant with Sanger sequencing, that targeted the L2-associated variants m.2416T>C (rs28358580, OR 1.2, p=0.02) and m.2332C>T (OR 1.2, p=.02) in MT-RNR2. Another variant within MT-RNR2, m.3010G>A (rs3928306), previously implicated in sensitivity to the optic neuropathy-associated antibiotic linezolid, and arising on D4 and J1 lineages, associated with Leber hereditary optic neuropathy (LHON) severity, was confirmed to be common (>5%) but was not significantly enriched in the POAG cases. Two variants linked to the composition of the gut microbiome, m.15784T>C (rs527236194, haplogroup L2a1) and m.16390G>A (rs41378955, L2 haplogroups), were also enriched in the case DNA pools.ConclusionsThese results implicate African mtDNA haplogroups L1c2, L1c2b, and L2 as risk factors for POAG. Approximately one in four African Americans have these mitochondrial ancestries, which may contribute to their elevated glaucoma risk. These haplogroups are defined in part by ancestral variants in the MT-RNR2 and/or MT-CO1 genes, several of which have prior disease associations, such as MT-CO1 missense variants that have been implicated in prostate cancer.

Project description:To facilitate whole-genome association studies (WGAS), several high-density SNP genotyping arrays have been developed. Genetic coverage and statistical power are the primary benchmark metrics in evaluating the performance of SNP arrays. Ideally, such evaluations would be done on a SNP set and a cohort of individuals that are both independently sampled from the original SNPs and individuals used in developing the arrays. Without utilization of an independent test set, previous estimates of genetic coverage and statistical power may be subject to an overfitting bias. Additionally, the SNP arrays' statistical power in WGAS has not been systematically assessed on real traits. One robust setting for doing so is to evaluate statistical power on thousands of traits measured from a single set of individuals. In this study, 359 newly sampled Americans of European descent were genotyped using both Affymetrix 500K (Affx500K) and Illumina 650Y (Ilmn650K) SNP arrays. From these data, we were able to obtain estimates of genetic coverage, which are robust to overfitting, by constructing an independent test set from among these genotypes and individuals. Furthermore, we collected liver tissue RNA from the participants and profiled these samples on a comprehensive gene expression microarray. The RNA levels were used as a large-scale set of quantitative traits to calibrate the relative statistical power of the commercial arrays. Our genetic coverage estimates are lower than previous reports, providing evidence that previous estimates may be inflated due to overfitting. The Ilmn650K platform showed reasonable power (50% or greater) to detect SNPs associated with quantitative traits when the signal-to-noise ratio (SNR) is greater than or equal to 0.5 and the causal SNP's minor allele frequency (MAF) is greater than or equal to 20% (N = 359). In testing each of the more than 40,000 gene expression traits for association to each of the SNPs on the Ilmn650K and Affx500K arrays, we found that the Ilmn650K yielded 15% times more discoveries than the Affx500K at the same false discovery rate (FDR) level.

Project description:BackgroundAdmixture mapping is a powerful approach for identifying genetic variants involved in human disease that exploits the unique genomic structure in recently admixed populations. To use existing published panels of ancestry-informative markers (AIMs) for admixture mapping, markers have to be genotyped de novo for each admixed study sample and samples representing the ancestral parental populations. The increased availability of dense marker data on commercial chips has made it feasible to develop panels wherein the markers need not be predetermined.ResultsWe developed two panels of AIMs (approximately 2,000 markers each) based on the Affymetrix Genome-Wide Human SNP Array 6.0 for admixture mapping with African American samples. These two AIM panels had good map power that was higher than that of a denser panel of approximately 20,000 random markers as well as other published panels of AIMs. As a test case, we applied the panels in an admixture mapping study of hypertension in African Americans in the Washington, D.C. metropolitan area.ConclusionsDeveloping marker panels for admixture mapping from existing genome-wide genotype data offers two major advantages: (1) no de novo genotyping needs to be done, thereby saving costs, and (2) markers can be filtered for various quality measures and replacement markers (to minimize gaps) can be selected at no additional cost. Panels of carefully selected AIMs have two major advantages over panels of random markers: (1) the map power from sparser panels of AIMs is higher than that of approximately 10-fold denser panels of random markers, and (2) clusters can be labeled based on information from the parental populations. With current technology, chip-based genome-wide genotyping is less expensive than genotyping approximately 20,000 random markers. The major advantage of using random markers is the absence of ascertainment effects resulting from the process of selecting markers. The ability to develop marker panels informative for ancestry from SNP chip genotype data provides a fresh opportunity to conduct admixture mapping for disease genes in admixed populations when genome-wide association data exist or are planned.

Dataset Information

The performance of common SNP arrays in assigning African mitochondrial haplogroups.

Background

Results

Conclusions

Publications

The performance of common SNP arrays in assigning African mitochondrial haplogroups.

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