The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies.

Vision begins in the retina at the rod and cone photoreceptors, which are sensory neurons with specialized visual pigments for capturing light quanta. Most mammals have one type of rod and two types of cone (M and S) photoreceptors that confer dichromatic vision. Humans have one type of rod and three cone subtypes that confer trichromacy. All retinal neurons, including photoreceptors, are generated from multipotent progenitor cells through a step-wise process that increasingly restricts lineage choices and commits cells to a particular fate. The balanced actions of six key transcription factors (the paired-type homeodomain transcription factor OTX2, cone–rod homeobox protein CRX, neural retina leucine zipper protein (NRL), photoreceptor-specific nuclear receptor (NR2E3), nuclear receptor RORβ and thyroid hormone receptor β2 (TRβ2)) are crucial as retinal progenitors commit to a rod or cone lineage. We propose a 'transcriptional dominance' model of photoreceptor fate determination that includes three fundamental attributes: that all photoreceptor types originate from a common postmitotic photoreceptor precursor that has the potential to form rods or any cone type; that such precursors differentiate by 'default' as S cones unless additional signals promote acquisition of a rod or M cone identity; and that the particular fate acquired by a precursor results from a contest among specific transcription factors. We predict that transcriptional signals control two key points during fate specification: first, the decision to form a rod or a cone — dictated by NRL and its downstream target NR2E3; second, the decision for a cone to acquire an S cone or M cone identity, largely determined by thyroid hormone receptor TRβ2. OTX2 and RORβ act upstream of NRL, whereas CRX induces both rod and cone genes during photoreceptor maturation. Abnormalities, dysfunction and/or death of photoreceptors constitute the primary cause of visual impairment or blindness in most retinal diseases. Many retinal disease genes are targets of the differentiation factors NRL, CRX and NR2E3, which also maintain rod homeostasis. Studies of transcriptional regulation underlying photoreceptor development should further advance gene- and small-molecule-based interventions and cell-based transplantation therapies for retinal degenerative diseases.

Genetic and genomic studies have enhanced our understanding of complex neurodegenerative diseases that exert a devastating impact on individuals and society. One such disease, age-related macular degeneration (AMD), is a major cause of progressive and debilitating visual impairment. Since the pioneering discovery in 2005 of complement factor H (CFH) as a major AMD susceptibility gene, extensive investigations have confirmed 19 additional genetic risk loci, and more are anticipated. In addition to common variants identified by now-conventional genome-wide association studies, targeted genomic sequencing and exome-chip analyses are uncovering rare variant alleles of high impact. Here, we provide a critical review of the ongoing genetic studies and of common and rare risk variants at a total of 20 susceptibility loci, which together explain 40–60% of the disease heritability but provide limited power for diagnostic testing of disease risk. Identification of these susceptibility loci has begun to untangle the complex biological pathways underlying AMD pathophysiology, pointing to new testable paradigms for treatment.