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.
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