Tasas de mutación estructural de novo y sesgos en los gametos de origen revelados mediante la secuenciación del genoma de 2,396 familias.

Each human genome includes de novo mutations that arose during
gametogenesis. While these germline mutations represent a fundamental
source of new genetic diversity, they can also create deleterious alleles
that impact fitness. Whereas the rate and patterns of point mutations in
the human germline are now well understood, far less is known about the
frequency and features that impact de novo structural variants (dnSVs). We
report a family-based study of germline mutations among 9,599 human genomes
de 33 multigenerational CEPH-Utah families and 2,384 families from the
Simons Foundation Autism Research Initiative. We find that de novo
structural mutations detected by alignment-based, short-read WGS occur at
an overall rate of at least 0.160 events per genome in unaffected
individuals, and we observe a significantly higher rate (0.206 per genome)
in ASD-affected individuals. In both probands and unaffected samples,
cerca de 73% of de novo structural mutations arose in paternal gametes, y
we predict most de novo structural mutations to be caused by mutational
mechanisms that do not require sequence homology. After multiple testing
correction, we did not observe a statistically significant correlation
between parental age and the rate of de novo structural variation in
offspring. These results highlight that a spectrum of mutational mechanisms
contribute to germline structural mutations and that these mechanisms most
likely have markedly different rates and selective pressures than those
leading to point mutations.