Genes are revealing our diversity

The sequencing of more and more genomes is showing not only how we differ from other animals but also how much we differ amongst ourselves, while large-scale efforts to scan the length of our DNA has pinpointed hundreds of genes linked to common diseases.

To understand more about some of the implications, OxSciBlog caught up with Julian Knight of the Wellcome Trust Centre for Human Genetics, who has just had a book published by OUP titled Human Genetic Diversity.

OxSciBlog: The Human Genome Project revealed one DNA sequence for all of humankind back in 2000. What’s happened since?
Julian Knight: The Human Genome Project was a remarkable scientific advance which has revolutionised genetics and biology. Armed with this route map or ‘blueprint’ of the human genome, scientists have since been able to study specific genes in the genome, understand how expression of genes is regulated and perhaps most importantly discover how we differ as individuals in our genetic makeup.

OSB: How do individuals vary genetically? Are we very diverse as a species?
JK: Although as a species we all share the great majority of our genetic sequence, there are important differences between individuals. This affects not only our physical appearance, but also how our normal physiology operates and our individual susceptibility to disease.

As technology has advanced, we have found that genetic diversity occurs more commonly than expected. This ranges from microscopically visible differences in chromosome number and structure, to very fine scale variation at the level of single DNA base differences – often described as ‘single nucleotide polymorphisms’ or ‘SNPs'.

There have been major efforts to understand this genetic diversity through collaborative studies such as the International HapMap Project and recently the 1000 Genomes Project which will give us a much more complete understanding of common and rare variants.

OSB: What do we know about genetic variations in different people and their susceptibility to disease?
JK: Genetic variation between people allows us to look for association with disease susceptibility. For some genetic variants, their effect is highly significant and typically they are rare in a population, leading to classical ‘genetic’ diseases showing Mendelian inheritance in families such as cystic fibrosis or Huntington’s disease. Linkage analysis has successfully identified the genetic basis of many such diseases.

More recently, the genetic contribution to common diseases such as type 1 diabetes or asthma have been established, based on genome-wide association studies using hundreds of thousands of SNP markers.

OSB: What has that taught us about the causes of disease and can we expect major advances in treatment as a result?
JK: The recent explosion in knowledge about the genetic basis of common diseases made possible by the genome-wide association study approach has provided important new insights into the basis of disease, as well as potential new drug targets. There are also remarkable opportunities for ‘personalised medicine’ in which therapies can be tailored to the individual patient to maximise benefit and minimise risk of adverse effects.

However our understanding of the genetic basis of susceptibility to diseases such as diabetes remains incomplete as to date we are only explaining a minority of the genetic risk.

OSB: Can we expect a time when it is routine to scan each of our genomes so we can receive drugs and treatment to fit our personal genetic profile?
JK: Personalised medicine based on genetic testing will become a routine part of healthcare but much work remains to be done to more fully understand the science, and to address the many social and ethical issues which arise. Already genetic testing is helping in the safe use of particular drugs, such as for treatment of HIV infection or use of the anticoagulant drug warfarin.

OSB: By tracing back genetic variation in humans, is it possible to learn more about our origins?
JK: The study of different types of genetic variation has been very informative in understanding our ancestral origins, both over recent generations but also in evolutionary timescales. For example, this has provided important supporting evidence for the proposed origins of anatomically modern humans in Africa, as well as particular selective pressures operating in human populations in the recent past, such as malarial infection.

OSB: And can we answer the question of whether humans are still evolving? Is there any evidence of selective pressures on the genetic variations we see?
JK: Genetic variation continues to arise and provides a substrate for ongoing evolution. Differences in the frequency of particular genetic variants and the combinations in which they occur can leave so-called ‘signatures of selection’ in particular regions of the human genome reflecting past selective pressures. This is well illustrated by lactase persistence, a trait which is found in different human populations related to dairy farming. Specific genetic variants involving the LCT gene are found to confer lactase persistence, for example in European populations.