Human genetics and genomics a decade after the release of the draft sequence of the human genome

Substantial progress has been made in human genetics and genomics research over the past 10 years since the publication of the draft sequence of the human genome [1,2]. The Human Genome Project (HGP) provided the basic raw DNA sequence that spawned a plethora of secondary studies which together greatly improved our knowledge of the architecture and function of the genome, yielding new insights with respect to (i) gene number and density, (ii) non-protein-coding RNA genes (or RNA genes), (iii) pervasive transcription, (iv) high copy number repeat sequences and (v) evolutionary conservation. These developments also have challenged the classical definition of the gene (see below).In parallel, the design of studies investigating complex diseases and traits has gradually shifted from candidate-gene association and linkage studies to genome-wide association studies (GWASs). The first proper GWAS study was published in 2005. This succeeded in identifying a common risk variant with a large effect size in the complement factor H (CFH) gene, which was associated with age-related macular degeneration [3]. By 2007, approximately 100 new GWASs had been published, relating to various complex diseases and traits [4]. There has, however, been some criticism of the inability of GWASs to identify many of the presumed disease-associated variants. Indeed, the validity of the common-disease common-variant (CD/CV) model has recently been challenged by virtue of the perceived 'missing heritability' [5-7]. This notwithstanding, the GWAS approach has dramatically changed the field of human disease genetics, from identifying mostly irreproducible disease associations in the pre-GWAS era to revealing thousands of statistically robust single nucleotide polymorphism (SNP) associations today [8-11]. The focus has also gradually shifted back to Mendelian disorders, with the advent of high-throughput sequence capture and sequencing technologies which have potentiated exome and whole-genome (re)seq