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Chapter 5 - Genetic Variation

from Section 1 - Principles Of Cellular And Molecular Biology

Published online by Cambridge University Press:  04 June 2019

Silke Arndt
Affiliation:
MSc, graduated in 1997 from the University of Bielefeld (Germany). She is currently employed as medical scientist and lecturer in the Division of Human Genetics at the National Health Laboratory Service (NHLS) and University of the Witwatersrand.
Anthony B Lane
Affiliation:
PhD, heads the Serogenetics Laboratory in the Division of Human Genetics, National Health Laboratory Service and School of Pathology, University of the Witwatersrand.
Barry Mendelow
Affiliation:
University of the Witwatersrand, Johannesburg
Michèle Ramsay
Affiliation:
University of the Witwatersrand, Johannesburg
Nanthakumarn Chetty
Affiliation:
University of the Witwatersrand, Johannesburg
Wendy Stevens
Affiliation:
University of the Witwatersrand, Johannesburg
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Summary

INTRODUCTION

If an average novel contains about 1000 words per page and the DNA nucleotide sequence of a single germ cell was printed as a book (each nucleotide as one letter), it would result in a tome of about half a million pages! There would be no page numbers, only ‘chapters’ equivalent to our chromosomes. In order to describe the exact position as well as the different kinds of ‘printing error’ that such a vast book may have, a set of universally applied rules is needed. This chapter reviews the spectrum of variation observed in the human genome and briefly outlines a nomenclature for its description specifically related to disease. The nomenclature is based on recommendations from the Human Genome Variation Society (HGVS) published in August 2006.

WHAT IS A VARIANT?

A variant is defined as a structural change in genomic DNA that can be transmitted from one cell to its daughter cell. Strictly speaking, mutational events in humans create new alleles, but in this chapter the term variant will be used in place of allele most of the time. It is general practice to use the term mutation when referring to pathogenic variants, though this is not strictly correct. The term mutation is rooted in the Latin verb mutare – to change – and it refers to any change observed in DNA, pathogenic and non-pathogenic.

HOW DO VARIANTS ARISE?

The main underlying mechanisms through which variants arise include chromosome breakage followed by the loss of DNA or incorrect joining of broken ends, recombination between misaligned chromosomes, gene conversion and errors made during DNA replication and DNA repair. Variants can arise from the incorporation of ‘wrong’ nucleotides during DNA replication, which can occur spontaneously or result from the presence of chemically modified bases in the template DNA. An additional source of variants is the slippage of nascent DNA strands along their template strands during DNA replication.

The rate at which variants are produced can be increased through exposure to mutagens present in the environment (e.g. UV radiation and chemical agents) as well as by the presence of ‘faulty’ DNA replication machinery (e.g. DNA polymerase) that does not copy or proofread newly formed DNA stringently.

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Publisher: Wits University Press
Print publication year: 2008

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  • Genetic Variation
    • By Silke Arndt, MSc, graduated in 1997 from the University of Bielefeld (Germany). She is currently employed as medical scientist and lecturer in the Division of Human Genetics at the National Health Laboratory Service (NHLS) and University of the Witwatersrand., Anthony B Lane, PhD, heads the Serogenetics Laboratory in the Division of Human Genetics, National Health Laboratory Service and School of Pathology, University of the Witwatersrand.
  • Edited by Barry Mendelow, University of the Witwatersrand, Johannesburg, Michèle Ramsay, University of the Witwatersrand, Johannesburg, Nanthakumarn Chetty, University of the Witwatersrand, Johannesburg, Wendy Stevens, University of the Witwatersrand, Johannesburg
  • Book: Molecular Medicine for Clinicians
  • Online publication: 04 June 2019
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  • Genetic Variation
    • By Silke Arndt, MSc, graduated in 1997 from the University of Bielefeld (Germany). She is currently employed as medical scientist and lecturer in the Division of Human Genetics at the National Health Laboratory Service (NHLS) and University of the Witwatersrand., Anthony B Lane, PhD, heads the Serogenetics Laboratory in the Division of Human Genetics, National Health Laboratory Service and School of Pathology, University of the Witwatersrand.
  • Edited by Barry Mendelow, University of the Witwatersrand, Johannesburg, Michèle Ramsay, University of the Witwatersrand, Johannesburg, Nanthakumarn Chetty, University of the Witwatersrand, Johannesburg, Wendy Stevens, University of the Witwatersrand, Johannesburg
  • Book: Molecular Medicine for Clinicians
  • Online publication: 04 June 2019
Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

  • Genetic Variation
    • By Silke Arndt, MSc, graduated in 1997 from the University of Bielefeld (Germany). She is currently employed as medical scientist and lecturer in the Division of Human Genetics at the National Health Laboratory Service (NHLS) and University of the Witwatersrand., Anthony B Lane, PhD, heads the Serogenetics Laboratory in the Division of Human Genetics, National Health Laboratory Service and School of Pathology, University of the Witwatersrand.
  • Edited by Barry Mendelow, University of the Witwatersrand, Johannesburg, Michèle Ramsay, University of the Witwatersrand, Johannesburg, Nanthakumarn Chetty, University of the Witwatersrand, Johannesburg, Wendy Stevens, University of the Witwatersrand, Johannesburg
  • Book: Molecular Medicine for Clinicians
  • Online publication: 04 June 2019
Available formats
×