Dataset Information

Marked variation in predicted and observed variability of tandem repeat loci across the human genome.

ABSTRACT:

Background

Tandem repeat (TR) variants in the human genome play key roles in a number of diseases. However, current models predicting variability are based on limited training sets. We conducted a systematic analysis of TRs of unit lengths 2-12 nucleotides in Whole Genome Shotgun (WGS) sequences to define the extent of variation of 209,214 unique repeat loci throughout the genome.

Results

We applied a multivariate statistical model to predict TR variability. Predicted heterozygosity correlated with heterozygosity in the CEPH polymorphism database (correlation rho = 0.29, p < 0.0005) better than the correlation between the CEPH and WGS data (rho = 0.17), presumably because the model smoothes noise from small sample sizes. A multivariate logistic model of 8 parameters accounted for 36% of the variation in the WGS data. Validation studies of 70 experimentally investigated TRs revealed high concordance with the model's predictions (p < 0.0001).

Conclusion

Variability among 2-12-mer TRs in the genome can be modeled by a few parameters, which do not markedly differ according to unit length, consistent with a common mechanism for the generation of variability among such TRs. Analysis of the distributions of observed and predicted variants across the genome showed a general concordance, indicating that the repeat variation dataset does not exhibit strong regional ascertainment biases. This revealed a deficit of variant repeats in chromosomes 19 and Y - likely to reflect a reduction in 2-mer repeats in the former and a reduced level of recombination in the latter - and excesses in chromosomes 6, 13, 20 and 21.

SUBMITTER: O'Dushlaine CT

PROVIDER: S-EPMC2364633 | biostudies-literature | 2008 Apr

REPOSITORIES: biostudies-literature

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Publications

Marked variation in predicted and observed variability of tandem repeat loci across the human genome.

O'Dushlaine Colm T CT Shields Denis C DC

BMC genomics 20080416

<h4>Background</h4>Tandem repeat (TR) variants in the human genome play key roles in a number of diseases. However, current models predicting variability are based on limited training sets. We conducted a systematic analysis of TRs of unit lengths 2-12 nucleotides in Whole Genome Shotgun (WGS) sequences to define the extent of variation of 209,214 unique repeat loci throughout the genome.<h4>Results</h4>We applied a multivariate statistical model to predict TR variability. Predicted heterozygosi ...[more]

PMID: 18416815

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Project description:The hepatitis B virus (HBV) exists as 9 major genotypes (A to I), one minor strain (designated J) and multiple subtypes. Marked differences in HBV natural history, disease progression and treatment response are exhibited by many of these genotypes and subtypes. For example, HBV genotype C is associated with later hepatitis B e antigen (HBeAg) seroconversion and high rates of liver cancer compared to other HBV genotypes, whereas genotype A2 is rarely associated with HBeAg-negative disease or liver cancer. The reasons for these and other differences in HBV natural history are yet to be determined but could in part be due to sequence differences in the HBV genome that alter replicative capacity and/or gene expression. Direct comparative studies on HBV replication and protein expression have been limited to date due largely to the absence of infectious HBV cDNA clones for each of the HBV genotypes present in the same genetic arrangement. We have produced replication-competent infectious cDNA clones of the most common subtypes of genotypes A to D, namely, A2, B2, C2, D3, and the minor strain J, and compared their HBV replication phenotype using transient-transfection models. We identified striking differences in HBV replicative capacity as well as HBeAg and surface (HBsAg) protein expression across genotypes, which may in part be due to sequence variability in regulatory regions of the HBV genome. Functional analysis showed that sequence differences in the major upstream regulatory region across genotypes impacted promoter activity.ImportanceThere have been very few studies directly comparing the replication phenotype of different HBV genotypes, for which there are marked differences in natural history and disease progression worldwide. We have generated replication-competent 1.3-mer cDNA clones of the major genotypes A2, B2, C2, and D3, as well as a recently identified strain J, and identified striking differences in replicative capacity and protein expression that may contribute to some of the observed differences in HBV natural history observed globally.

Dataset Information

Marked variation in predicted and observed variability of tandem repeat loci across the human genome.

Background

Results

Conclusion

Publications

Marked variation in predicted and observed variability of tandem repeat loci across the human genome.

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