There is a danger when the pace of change is so fast, and the discoveries so remarkable, that we can lose sight of lessons learned in the past and the broader context of a field of scientific research. For human genetics, advances over the last twenty years since I studied as a medical student have been nothing short of revolutionary, changing what had been regarded as a sleepy backwater in the medical curriculum into a leading light, radically advancing our understanding of the basis of disease. The ramifications of contemporary genetic research extend far beyond medicine however, providing fundamental insights into biology and human origins, as well as important questions about the individual and society. This book was written as an introduction to the nature and functional consequences of human genetic variation, aiming to convey some of the excitement associated with recent advances by reviewing cutting-edge research while also providing a broad biological and historical context by considering some of the many landmark papers in the field.
The book begins with a review of the pioneering work into variation involving the genes encoding haemoglobin which has provided many fundamental insights into this field of research. Chapter 1 also serves to provide a primer in molecular genetics with examples given of the different types of genetic variation found at the globin gene loci, and more widely across the genome through the remarkable efforts to sequence the human genome. The major classes of genetic variation are then reviewed in more detail, ranging from the cytogenetically visible structural genomic variation seen at a microscopic chromosomal level (Chapter 3) to smaller scale submicroscopic structural variation which is increasingly recognised as copy number variation among healthy individuals as well as contributing to common multifactorial diseases (Chapter 4) and genomic disorders (Chapter 5). The origins and role of segmental duplications in evolution and structural variation are described (Chapter 6) as well as the remarkable insights and application of research into tandem repeats (Chapter 7) and mobile DNA elements (Chapter 8). Sequence level diversity is then described including the efforts to catalogue and define the genomic architecture of such variation with implications for understanding susceptibility to common disease (Chapter 9) and selective pressures operating in our evolutionary and recent past (Chapter 10). Approaches to dissecting the genetic basis of classical mendelian diseases as well as common multifactorial traits are described, ranging from linkage and positional cloning to current genome-wide association studies (Chapters 2 and 9). Much remains to be understood about how genetic variants may be acting at a molecular level to modulate the nature or function of the protein encoded by a gene or the levels of expression of the gene itself, a topic explored in Chapter 11. Many of the successes and current roadblocks in our understanding of the nature and consequences of human genetic diversity are then highlighted by the extreme diversity found at the major histocompatibility complex on chromosome 6 (Chapter 12) while the past and ongoing battles seen in major parasitic diseases such as malaria (Chapter 13) and human immunodeficiency virus (Chapter 14) show how human genetic diversity reflects in part a genomic battlefield where specific allelic variants may change in frequency dependent on particular selection pressures.
The text is deliberately focused on exploring specific examples to illustrate the field rather than aiming to be comprehensive, and I hope that the references and reviews cited will serve as a jumping point for further reading. The glossary explains some of the more technical subject matter, with terms highlighted in bold on first mention in the text.
I hope that this will serve to make the book accessible and informative, of relevance to the practicing clinician, as well as to the specialist researcher, and to medical students and others studying at an advanced undergraduate and graduate level. The subject matter encompasses the many disciplines impacted by human genetic diversity, ranging from medicine to evolutionary biology, biological anthropology and molecular biology. These are times of dramatic scientific advances in human genetics that will impact on us all as individuals and as a society, and important choices lie ahead in how we choose to use such knowledge. If this book can go a small way towards conveying the excitement felt in contemporary research into human genetic variation, and the breadth of its application, then it will have succeeded, and done so by dint of the remarkable nature of the subject matter more than by my own efforts.
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