Missing heritability: Paternal age effect mutations and selfish spermatogonia

Nature Reviews Genetics (Impact Factor: 36.98). 08/2010; 11(8):589. DOI: 10.1038/nrg2809-c1
Source: PubMed
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    • "In 2010, Goriely and Wilkie highlighted that paternal age effect (PAE) mutations are an emerging mechanism contributing to the introduction of new disease alleles into the population. PAE mutations mostly encode mutant proteins with gain-of-function properties, are of near-exclusive paternal origin, occur at elevated paternal ages and have an apparent germline mutation rate [44]. Interestingly, PAE mutations have been reported in various craniosynostosis syndromes caused by mutations in FGFR2 and FGFR3. "
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    PLoS ONE 03/2013; 8(3):e60264. DOI:10.1371/journal.pone.0060264 · 3.23 Impact Factor
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    ABSTRACT: Contemporary sequencing studies often ignore the diploid nature of the human genome because they do not routinely separate or 'phase' maternally and paternally derived sequence information. However, many findings - both from recent studies and in the more established medical genetics literature - indicate that relationships between human DNA sequence and phenotype, including disease, can be more fully understood with phase information. Thus, the existing technological impediments to obtaining phase information must be overcome if human genomics is to reach its full potential.
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    ABSTRACT: Rare de novo genetic variants have been detected in a number of diseases using case-parent trios. So far, trio studies have largely been confined to early-onset diseases where parent DNA samples are readily available. To test the feasibility of finding rare de novo variants in a typical late-onset neurodegenerative disease, we compared genome-wide copy number variants (CNVs) between patients with sporadic amyotrophic lateral sclerosis (SALS) and their unaffected parents. DNA from 12 SALS patients and their 24 parents was analysed for CNVs using AffyMetrix SNP 6.0 microarrays and Partek software. De novo CNVs (present in patients but not their parents) considered likely candidates for SALS were those that overlapped with CNS-related genes, were rare, or were found in multiple patients. All SALS patients had de novo CNVs. In 11 patients, 37 de novo CNVs fulfilled one or more criteria for a candidate region. Eleven de novo CNVs overlapped with genes, some of which are in pathways suspected in the pathogenesis of SALS. In conclusion, this pilot study shows that trios can be used to look for rare de novo genetic variants in patients with late adult-onset neurodegenerative disease. The results suggest that further studies of this nature with larger numbers of trios are warranted, but it is unusual to find surviving parents of offspring who have a late-onset neurodegenerative disease. An international collaborative effort will therefore be needed to collect sufficient numbers of such trios to reliably detect de novo mutations underlying these diseases.
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