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Brief Funct Genomic Proteomic. Author manuscript; available in PMC 2010 November 2.
Published in final edited form as:
Brief Funct Genomic Proteomic. 2009 September; 8(5): 343–344.
doi:  10.1093/bfgp/elp039
PMCID: PMC2967738


While it is true that recent advances in human genetics research have radically advanced our understanding of the nature and consequences of human genetic diversity, the extent of the challenges remaining to uncover the many secrets still closely guarded within our variable genomes has also become clear. However thanks to pioneering research involving international collaborative efforts such as the Human Genome Project [1] and a series of technological breakthroughs, we now have both a route map of the human genome and at least some insight into the myriad ways in which our individual genomes vary, within and between human populations, and in relation to other species.

As our ability to sequence DNA and genotype different classes of genetic marker have advanced, researchers have sought to understand genetic variation at a nucleotide level. Research efforts such as the International HapMap Project ( have provided fundamental insights into the remarkable diversity that exists and the underlying allelic architecture within populations. Such work has ushered in the era of the SNP (single nucleotide polymorphism), superseding highly polymorphic markers such as variable number tandem repeats by virtue of the ability to perform high throughput genotyping for hundreds of thousands of common informative SNP markers across the genome and so making approaches such as genome-wide association studies a feasible option in efforts to understand the genetic contribution to common multifactorial traits [2, 3].

In this issue of Briefings in Functional Genomics and Proteomics, Kalliope Panoutsopoulou and Eleftheria Zeggini give a historical overview of the key developments which have led to the recent successes of genome-wide association studies in complex diseases such as type 2 diabetes, building on earlier work using linkage analysis and candidate gene association studies. They also highlight the challenges remaining, as to date we are only explaining a small minority of the postulated attributable genetic risk in such diseases, even with the powerful tools currently available. This has led to calls for ever larger sample sizes, to increase study power to detect the many common variants associated with modest effect sizes believed to be responsible for a significant proportion of the genetic risk in complex traits [4].

Rare variants are also likely to play critical role in common disease, and recent advances in next-generation or ultra-high throughput sequencing look set to further revolutionise our understanding of the extent of genetic variation and its role in human disease. Collaborative research efforts such as the 1000 genomes project ( will provide a taste of the future in this field, while the many different technological approaches under development to further reduce cost and increase throughput, will likely ensure that current genotyping efforts using microarray platforms become superseded by resequencing in the near future. The remarkable progress in this field is reviewed here by Kalim Mir, highlighting the applications, challenges and future direction of work in this area.

Technological advances have also played a critical role in our appreciation of the extent and nature of structural genomic variation. Techniques such as comparative genome hybridisation using microarrays have allowed the detection of progressively smaller structural variants, highlighting how common such variation is within ‘normal’ human populations and its role in disease [5, 6]. Copy number variation has been shown to play a critical role in a diverse range of conditions, from learning disability to Parkinson’s disease and HIV-1 infection [7]. Laura Winchester, Christopher Yau and Ioannis Ragoussis highlight the importance of copy number variation and the currently available methods for detection, describing in detail analysis of SNP genotyping data to detect copy number events.

The complexities of genetic variation are still being unravelled at many different levels. Many insights have been gained from intensive research at particular genomic loci such as the Major Histocompatibility Complex (MHC) at chromosome 6p21. A historical overview of the research which has defined the remarkable genomic landscape spanned by the MHC is given by Claire Vandiedonck and myself in this issue, highlighting the extreme polymorphism found in this region and the very strong associations with susceptibility to autoimmune, infectious and inflammatory diseases. Research into meiotic recombination and the coinheritance of genetic markers within the MHC has been instrumental in the development of key concepts such as linkage disequilibrium and haplotypic structure, while the MHC was the first substantial genomic region to be resequenced.

Despite intensive effort, the basis of observed associations of genetic markers in the MHC and elsewhere in the genome with disease remains in most cases unknown. To resolve this further will require intensive efforts in fine mapping and functional studies are required to more clearly understand the consequences of possessing specific genetic variants, for example at a structural level in terms of the encoded protein or for gene regulation [8]. Work in this area is revealing a highly complex scenario, overlaid by epistatic and epigenetic mechanisms, such that we begin to see how environmental and genetic factors may be interacting to result in a particular phenotype. Our appreciation of the many different control mechanisms operating to regulate gene expression continues to grow, and assessment of the functional consequences of specific genetic variants will be require careful context-specific analysis in relation to a particular cell or tissue type, and environmental stimulus.

The implications of the current ‘genetic revolution’ in our understanding of human genetic diversity will likely have dramatic consequences for personalised health care, our understanding of disease pathogenesis and drug development. However the applications of current genetic approaches go far beyond medicine, providing radical new insights into human origins and society as illustrated by the paper by Qasim Ayub and Chris Tyler-Smith in this issue relating to genetic variation in South Asian populations. This work highlights the many different forces which have shaped the observed contemporary patterns of genetic diversity in this remarkable region of the world, relating to geography, language, religious and historical factors. Current genetic advances have informed a growing number of diverse academic disciplines; it is important that in turn, human geneticists appreciate and integrate the novel insights which work in such subjects can provide, so that we can develop a full appreciation of the remarkable diversity of our variable genomes and its consequences for health and disease.


Publisher's Disclaimer: This is a pre-copyediting, author-produced pdf of an article accepted for publication in Briefings in Functional Genomics and Proteomics following peer review. The definitive publisher-authenticated version Knight JC Briefings in Functional Genomics 2009 8(5):343-344 is available at


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