The promise and reality of personal genomics

The second personal genome sequence of a Korean tells something about genetic ancestry but still little of medical relevance

Evidence that autosomal recessive spastic cerebral palsy-1 (CPSQ1) is caused by a missense variant in HPDL.

A subset of individuals diagnosed with cerebral palsy will have an underlying genetic diagnosis. Previously, a missense variant in GAD1 was described as a candidate mutation in a single family diagnosed with autosomal recessive spastic cerebral palsy-1 (CPSQ1; OMIM 603513). Following the ascertainment of a further branch of the CPSQ1 kindred, we found that the previously reported GAD1 variant did not segregate with the neurological disease phenotype in the recently ascertained branch of the kindred. Following genetic linkage studies to map autozygous regions and whole-exome sequencing, a missense variant (c.527 T > C; p. Leu176Pro, rs773333490) in the HPDL gene was detected and found to segregate with disease status in both branches of the kindred. HPDL encodes a 371-amino acid protein (4-Hydroxyphenylpyruvate Dioxygenase Like) that localizes to mitochondria but whose function is uncertain. Recently, biallelic loss of function variants and missense substitution-causing variants in HPDL were reported to cause a childhood onset progressive spastic movement disorder with a variable presentation. These findings suggest that HPDL-related neurological disease may mimic spastic cerebral palsy and that GAD1 should not be included in diagnostic gene panels for inherited cerebral palsy.NIH

Frequency of pathogenic germline variants in cancer susceptibility genes in 1336 renal cell carcinoma cases

Background Renal cell carcinoma (RCC) occurs in a number of cancer predisposition syndromes but the genetic architecture of susceptibility to RCC is not well defined. We investigated the frequency of pathogenic germline variants in cancer susceptibility genes (CSGs) within a large series of unselected RCC participants. Methods Whole genome sequencing data on 1336 RCC participants and 5834 controls recruited to the UK 100000 Genomes Project, a nationwide multicentre study, was analysed to identify rare pathogenic or likely pathogenic (P/LP) short variants (SNVs and INDELs) and structural variants in 121 CSGs. Results Among 1336 RCC participants (mean 61.3 years [±12SD], range 13–88 years; 64% male), 85 participants (6.4%; 95% CI [5.1, 7.8]) had one or more P/LP germline variant in a wider range of CSGs than previously recognised. A further 64 intragenic variants in CSGs previously associated with RCC were classified as a variant of uncertain significance (VUS) (24 ‘hot VUSs’) and were considered to be of potential clinical relevance as further evaluation might result in their reclassification. Most patients with pathogenic variants in well-established RCC-CSGs were aged < 50 years. Burden test analysis for filtered variants in CSGs demonstrated a significant excess of CHEK2 variants RCC European participants compared to the healthy European controls (P = 0.0019). Conclusions Approximately 6% of patients with RCC unselected for family history have a germline variant requiring additional follow-up analysis. To improve diagnostic yield we suggest expanding the panel of RCC-CSGs tested to include CHEK2 and all SDHx subunits and raising the eligibility criteria for age-based testing

Insights into hominid evolution from the gorilla genome sequence.

Gorillas are humans' closest living relatives after chimpanzees, and are of comparable importance for the study of human origins and evolution. Here we present the assembly and analysis of a genome sequence for the western lowland gorilla, and compare the whole genomes of all extant great ape genera. We propose a synthesis of genetic and fossil evidence consistent with placing the human-chimpanzee and human-chimpanzee-gorilla speciation events at approximately 6 and 10 million years ago. In 30% of the genome, gorilla is closer to human or chimpanzee than the latter are to each other; this is rarer around coding genes, indicating pervasive selection throughout great ape evolution, and has functional consequences in gene expression. A comparison of protein coding genes reveals approximately 500 genes showing accelerated evolution on each of the gorilla, human and chimpanzee lineages, and evidence for parallel acceleration, particularly of genes involved in hearing. We also compare the western and eastern gorilla species, estimating an average sequence divergence time 1.75 million years ago, but with evidence for more recent genetic exchange and a population bottleneck in the eastern species. The use of the genome sequence in these and future analyses will promote a deeper understanding of great ape biology and evolution

A Genome-Wide Survey of Genetic Variation in Gorillas Using Reduced Representation Sequencing

<div><p>All non-human great apes are endangered in the wild, and it is therefore important to gain an understanding of their demography and genetic diversity. Whole genome assembly projects have provided an invaluable foundation for understanding genetics in all four genera, but to date genetic studies of multiple individuals within great ape species have largely been confined to mitochondrial DNA and a small number of other loci. Here, we present a genome-wide survey of genetic variation in gorillas using a reduced representation sequencing approach, focusing on the two lowland subspecies. We identify 3,006,670 polymorphic sites in 14 individuals: 12 western lowland gorillas (<i>Gorilla gorilla gorilla</i>) and 2 eastern lowland gorillas (<i>Gorilla beringei graueri</i>). We find that the two species are genetically distinct, based on levels of heterozygosity and patterns of allele sharing. Focusing on the western lowland population, we observe evidence for population substructure, and a deficit of rare genetic variants suggesting a recent episode of population contraction. In western lowland gorillas, there is an elevation of variation towards telomeres and centromeres on the chromosomal scale. On a finer scale, we find substantial variation in genetic diversity, including a marked reduction close to the major histocompatibility locus, perhaps indicative of recent strong selection there. These findings suggest that despite their maintaining an overall level of genetic diversity equal to or greater than that of humans, population decline, perhaps associated with disease, has been a significant factor in recent and long-term pressures on wild gorilla populations.</p></div

Segregating sites in nine western lowland gorillas.

<p>A. Density of segregating sites in 1 Mbp bins. Sites passing quality and depth filtering thresholds in all nine gorillas BiKira, EB(JC), Fubu, Guy, Kamilah, Kesho, Matadi, Murphy and Ruby were binned in 1 Mb bins and the density of segregating sites calculated. Resulting densities are plotted on an ideogram, with the scale expressed as number of sites per kbp. B. Profile of mean segregating site density as a function of chromosomal position on both long and short arms, averaged over all chromosomes. Position is normalised by chromosome length, with the centromere at 0.0 and the telomere at 1.0 on both arms. An increase in genetic diversity is evident towards the centromere and telomere on both arms.</p

Principal components analysis (PCA).

<p>A. PCA based on 123,591 polymorphic sites in 12 western lowland gorillas and two eastern lowland gorillas. Here, PC1 separates western gorillas from eastern gorillas. B. PCA based on 110,971 polymorphic sites in the 12 western lowland gorillas only.</p