Identifying human disease genes through cross-species gene mapping of evolutionary conserved processes

Martin Poot, Alexandra Badea, Robert Williams, Martien J. Kas

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Background: Understanding complex networks that modulate development in humans is hampered by genetic and phenotypic heterogeneity within and between populations. Here we present a method that exploits natural variation in highly diverse mouse genetic reference panels in which genetic and environmental factors can be tightly controlled. The aim of our study is to test a cross-species genetic mapping strategy, which compares data of gene mapping in human patients with functional data obtained by QTL mapping in recombinant inbred mouse strains in order to prioritize human disease candidate genes. Methodology: We exploit evolutionary conservation of developmental phenotypes to discover gene variants that influence brain development in humans. We studied corpus callosum volume in a recombinant inbred mouse panel (C57BL/6J×DBA/2J, BXD strains) using high-field strength MRI technology. We aligned mouse mapping results for this neuro-anatomical phenotype with genetic data from patients with abnormal corpus callosum (ACC) development. Principal Findings: From the 61 syndromes which involve an ACC, 51 human candidate genes have been identified. Through interval mapping, we identified a single significant QTL on mouse chromosome 7 for corpus callosum volume with a QTL peak located between 25.5 and 26.7 Mb. Comparing the genes in this mouse QTL region with those associated with human syndromes (involving ACC) and those covered by copy number variations (CNV) yielded a single overlap, namely HNRPU in humans and Hnrpul1 in mice. Further analysis of corpus callosum volume in BXD strains revealed that the corpus callosum was significantly larger in BXD mice with a B genotype at the Hnrpul1 locus than in BXD mice with a D genotype at Hnrpul1 (F = 22.48, p<9.87*10-5). Conclusion: This approach that exploits highly diverse mouse strains provides an efficient and effective translational bridge to study the etiology of human developmental disorders, such as autism and schizophrenia.

Original languageEnglish (US)
Article numbere18612
JournalPLoS One
Volume6
Issue number5
DOIs
StatePublished - May 13 2011

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Chromosome Mapping
Corpus Callosum
human diseases
chromosome mapping
Genes
mice
genes
quantitative trait loci
Human Development
human development
Complex networks
Chromosomes
Magnetic resonance imaging
Genetic Crosses
Genotype
Conservation
Brain
Phenotype
Inbred Strains Mice
Chromosomes, Human, Pair 7

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Identifying human disease genes through cross-species gene mapping of evolutionary conserved processes. / Poot, Martin; Badea, Alexandra; Williams, Robert; Kas, Martien J.

In: PLoS One, Vol. 6, No. 5, e18612, 13.05.2011.

Research output: Contribution to journalArticle

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