|
Notas:
|
Curs 2012-2013
Several studies over the last few years have shown that newly arising (de novo) mutations
contribute to the genetics of schizophrenia (SZ), autism (ASD) and other developmental disorders.
The strongest evidence comes from studies of de novo Copy Number Variation (CNV), where the
rate of new mutations is shown to be increased in cases when compared to controls [23, 24]. Research
on de novo point mutations and small insertion-deletions (indels) has been more limited, but with
the development of next-generation sequencing (NGS) technology, such studies are beginning to
provide preliminary evidence that de novo single-nucleotide mutations (SNVs) might also increase
risk of SZ and ASD [25, 26]
Advanced paternal age is a major source of new mutations in human beings [27] and could thus be
associated with increased risk for developing SZ, ASD or other developmental disorders. Indeed,
advanced paternal age is found to be a risk factor for developing SZ and ASD in the offspring [28, 29]
and new mutations related to advanced paternal age have been implicated as a cause of sporadic
cases in several autosomal dominant diseases, some neurodevelopmental diseases, including SZ and
ASD, and social functioning. New single-base substitutions occur at higher rates at males compared
to females and this difference increases with paternal age. This is due to the fact that sperm cells go
through a much higher number of cell divisions (~840 by the age of 50), which increases the risk for
DNA copy errors in the male germ line [30] . By contrast, the female eggs (oocytes) undergo only 24
cell divisions and all but the last occur during foetal life.
The aim of my project is to determine the parent-of-origin of de novo SNVs, using large samples of
parent-offspring trios affected with schizophrenia (SZ). From whole exome sequencing of 618
Bulgarian proband-offspring trios affected, nearly 1000 de novo (SNVs or small indels) have been
identified and from these, the parent-of-origin of at least 60% of the mutations (N=600) can be
established. This project is contained in a main one that consists on the determination of the
parental origin of different types of de novo mutations (SNVs, small indels and large CNVs). |
