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Variation in genome-wide mutation rates within and between human families.

ABSTRACT: J.B.S. Haldane proposed in 1947 that the male germline may be more mutagenic than the female germline. Diverse studies have supported Haldane's contention of a higher average mutation rate in the male germline in a variety of mammals, including humans. Here we present, to our knowledge, the first direct comparative analysis of male and female germline mutation rates from the complete genome sequences of two parent-offspring trios. Through extensive validation, we identified 49 and 35 germline de novo mutations (DNMs) in two trio offspring, as well as 1,586 non-germline DNMs arising either somatically or in the cell lines from which the DNA was derived. Most strikingly, in one family, we observed that 92% of germline DNMs were from the paternal germline, whereas, in contrast, in the other family, 64% of DNMs were from the maternal germline. These observations suggest considerable variation in mutation rates within and between families.

SUBMITTER: Conrad DF

PROVIDER: S-EPMC3322360 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Variation in genome-wide mutation rates within and between human families.

Conrad Donald F DF Keebler Jonathan E M JE DePristo Mark A MA Lindsay Sarah J SJ Zhang Yujun Y Casals Ferran F Idaghdour Youssef Y Hartl Chris L CL Torroja Carlos C Garimella Kiran V KV Zilversmit Martine M Cartwright Reed R Rouleau Guy A GA Daly Mark M Stone Eric A EA Hurles Matthew E ME Awadalla Philip P

Nature genetics 20110612 7

J.B.S. Haldane proposed in 1947 that the male germline may be more mutagenic than the female germline. Diverse studies have supported Haldane's contention of a higher average mutation rate in the male germline in a variety of mammals, including humans. Here we present, to our knowledge, the first direct comparative analysis of male and female germline mutation rates from the complete genome sequences of two parent-offspring trios. Through extensive validation, we identified 49 and 35 germline de ...[more]

PMID: 21666693

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Project description:BACKGROUND: Pompe disease has a broad clinical spectrum, in which the phenotype is partially explained by the genotype. The aim of this study was to describe phenotypical variation among siblings with non-classic Pompe disease. We hypothesized that siblings and families with the same genotype share more similar phenotypes than the total population of non-classic Pompe patients, and that this might reveal genotype-phenotype correlations. METHODS: We identified all Dutch families in which two or three siblings were diagnosed with Pompe disease and described genotype, acid ?-glucosidase activity, age at symptom onset, presenting symptoms, specific clinical features, mobility and ventilator dependency. RESULTS: We identified 22 families comprising two or three siblings. All carried the most common mutation c.-32-13 T > G in combination with another pathogenic mutation. The median age at symptom onset was 33 years (range 1-62 years). Within sibships symptom onset was either in childhood or in adulthood. The median variation in symptom onset between siblings was nine years (range 0-31 years). Presenting symptoms were similar across siblings in 14 out of 22 families. Limb girdle weakness was most frequently reported. In some families ptosis or bulbar weakness were present in all siblings. A large variation in disease severity (based on wheelchair/ventilator dependency) was observed in 11 families. This variation did not always result from a difference in duration of the disease since a third of the less affected siblings had a longer course of the disease. Enzyme activity could not explain this variation either. In most families male patients were more severely affected. Finally, symptom onset varied substantially in twelve families despite the same GAA genotype. CONCLUSION: In most families with non-classic Pompe disease siblings share a similar phenotype regarding symptom onset, presenting symptoms and specific clinical features. However, in some families the course and severity of disease varied substantially. This phenotypical variation was also observed in families with identical GAA genotypes. The commonalities and differences indicate that besides genotype, other factors such as epigenetic and environmental effects influence the clinical presentation and disease course.

Dataset Information

Variation in genome-wide mutation rates within and between human families.

Publications

Variation in genome-wide mutation rates within and between human families.

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