Individuals with severe, sporadic disorders of infantile onset represent an important class of disease for which discovery of the underlying genetic architecture is not amenable to traditional genetic analysis. Full-genome sequencing of affected individuals and their parents provides a powerful alternative strategy for gene discovery. We performed whole-genome sequencing (WGS) on a family quartet containing an affected proband and her unaffected parents and sibling. The 15-year-old female proband had a severe epileptic encephalopathy consisting of early-onset seizures, features of autism, intellectual disability, ataxia, and sudden unexplained death in epilepsy. We discovered a de novo heterozygous missense mutation (c.5302A>G [p.Asn1768Asp]) in the voltage-gated sodium-channel gene SCN8A in the proband. This mutation alters an evolutionarily conserved residue in Nav1.6, one of the most abundant sodium channels in the brain. Analysis of the biophysical properties of the mutant channel demonstrated a dramatic increase in persistent sodium current, incomplete channel inactivation, and a depolarizing shift in the voltage dependence of steady-state fast inactivation. Current-clamp analysis in hippocampal neurons transfected with p.Asn1768Asp channels revealed increased spontaneous firing, paroxysmal-depolarizing-shift-like complexes, and an increased firing frequency, consistent with a dominant gain-of-function phenotype in the heterozygous proband. This work identifies SCN8A as the fifth sodium-channel gene to be mutated in epilepsy and demonstrates the value of WGS for the identification of pathogenic mutations causing severe, sporadic neurological disorders.

Oculocutaneous albinism (OCA) is a genetically heterogeneous disorder. There are four known types of OCA: OCA1-OCA4. The clinical manifestations of all types of OCA include skin and hair hypopigmentation and visual impairment. Although there are a few documented observations of high frequency of albinism among Native Americans, including the Hopi, Zuni, Kuna, Jemez, Laguna, San Juan, and Navajo, no causative molecular defect has been previously reported. In the present study, we show that albinism in one Native American population, the Navajo, is caused by a LINE-mediated 122.5-kilobase deletion of the P gene, thus demonstrating that albinism in this population is OCA2. This deletion appears to be Navajo specific, because this allele was not detected in 34 other individuals with albinism who listed other Native American origins, nor has it been reported in any other ethnic group. The molecular characterization of this deletion allele allowed us to design a three-primer polymerase chain reaction system to estimate the carrier frequency in the Navajo population by screening 134 unrelated normally pigmented Navajos. The carrier frequency was found to be approximately 4.5%. The estimated prevalence of OCA2 in Navajos is between approximately 1 per 1,500 and 1 per 2,000. We further estimate that this mutation originated 400-1,000 years ago from a single founder.

Signals of archaic admixture have been identified through comparisons of the draft Neanderthal and Denisova genomes with those of living humans. Studies of individual loci contributing to these genome-wide average signals are required for characterization of the introgression process and investigation of whether archaic variants conferred an adaptive advantage to the ancestors of contemporary human populations. However, no definitive case of adaptive introgression has yet been described. Here we provide a DNA sequence analysis of the innate immune gene STAT2 and show that a haplotype carried by many Eurasians (but not sub-Saharan Africans) has a sequence that closely matches that of the Neanderthal STAT2. This haplotype, referred to as N, was discovered through a resequencing survey of the entire coding region of STAT2 in a global sample of 90 individuals. Analyses of publicly available complete genome sequence data show that haplotype N shares a recent common ancestor with the Neanderthal sequence (~80 thousand years ago) and is found throughout Eurasia at an average frequency of ~5%. Interestingly, N is found in Melanesian populations at ~10-fold higher frequency (~54%) than in Eurasian populations. A neutrality test that controls for demography rejects the hypothesis that a variant of N rose to high frequency in Melanesia by genetic drift alone. Although we are not able to pinpoint the precise target of positive selection, we identify nonsynonymous mutations in ERBB3, ESYT1, and STAT2-all of which are part of the same 250 kb introgressive haplotype-as good candidates.

We report the discovery of an African American Y chromosome that carries the ancestral state of all SNPs that defined the basal portion of the Y chromosome phylogenetic tree. We sequenced ∼240 kb of this chromosome to identify private, derived mutations on this lineage, which we named A00. We then estimated the time to the most recent common ancestor (TMRCA) for the Y tree as 338 thousand years ago (kya) (95% confidence interval = 237-581 kya). Remarkably, this exceeds current estimates of the mtDNA TMRCA, as well as those of the age of the oldest anatomically modern human fossils. The extremely ancient age combined with the rarity of the A00 lineage, which we also find at very low frequency in central Africa, point to the importance of considering more complex models for the origin of Y chromosome diversity. These models include ancient population structure and the possibility of archaic introgression of Y chromosomes into anatomically modern humans. The A00 lineage was discovered in a large database of consumer samples of African Americans and has not been identified in traditional hunter-gatherer populations from sub-Saharan Africa. This underscores how the stochastic nature of the genealogical process can affect inference from a single locus and warrants caution during the interpretation of the geographic location of divergent branches of the Y chromosome phylogenetic tree for the elucidation of human origins.