About this book
Our genome consists of DNA molecules with a combined length of over 3 billion nucleotides, which contains over 20,000 protein-coding genes, each encoding either one protein or a set of similar proteins – and these genes and proteins interact with each other, forming mind-boggling networks of mutual influences. A human body, which develops on the basis of instructions provided by the genome, consists of billions of cells, also engaged in complex interactions. In particular, the human brain contains 100 billion of neurons, and a similar number of glial cells, and a typical neuron communicates directly with thousands other neurons. A mutation which replaces just a single nucleotide may cause synthesis of a dysfunctional protein, and this can be fatal, or cause a severe disease, or have just a mild effect. Thus, deleterious mutations vastly outnumber beneficial mutations. Far from being a moot point, our vulnerability is constantly exposed by a relentless pressure of spontaneous mutation. Despite all the efforts of our cells to handle their DNA carefully, a newborn human receives, from their parents, on average, 60 new mutations, and about 10% of them impair the fitness substantially. So far, no means of reducing the rate of human spontaneous mutation have been discovered. Over 1% of newborns suffer a clear cut disease, including a wide variety of so-called Mendelian diseases, as well as schizophrenia, mental retardation, or severe autism due to new mutations in their genotypes. Milder, but still substantial, effects of new mutations are harder to detect but likely are even more pervasive.
Under natural conditions, natural selection prevents accumulation of deleterious mutations with cruel efficiency. However, in societies where clean water, food, shelter, and advanced medicine are available, only the most severe mutations preclude reproduction of a human. In other words, in industrialized countries, natural selection against deleterious mutations is much weaker than it used to be at any point during the 3,500+ million years of the evolutionary history of our ancestral lineage. Charles Darwin, the discoverer of evolution by natural selection, immediately realized that this is bound to lead to undesirable consequences. After the basic laws of heredity were discovered in the early 20th century, a number of geneticists, including Hermann Muller and James Crow, developed a framework for studying the effect of deleterious mutations on individual humans and on human populations. However, until very recently, estimates of the scale of the problem were rather fuzzy.
The recent flood of genomic data has begun to change this situation. The role of deleterious mutation in human variation and disease, and the potential consequences of unchecked accumulation of deleterious alleles, can be now discussed with much more confidence than even 10 years ago. Still, substantial uncertainties remain, but postgenomic biology will likely remove many of them in the next 20-30 years. Crumbling Genome will appeal to researchers interested in the ties between genetics and evolution, how these ties may influence social issues and human health.
Contents
Introduction: Everything consisting of parts crumbles
1. Genotypes and phenotypes
a) DNA is a text
b) Genomes small and large
c) Genes and intergenic regions
d) Cells, mitosis, and meiosis
e) From genotype to phenotype
2. Mendelian inheritance and population genetics
a) Inheritance is discrete
b) Populations are genetically variable
c) Loci and genes
d) Effects of alleles on phenotypes
e) Mendelian traits and diseases
3. Complex traits and their inheritance
a) Inheritance of phenotypes
b) Two-state traits and quantitative traits
c) Complex traits in the population
d) Effects of heredity and environment on complex traits
e) Polymorphic loci behind complex variation
4. Unavoidable mutation
a) Origin of genetic variation
b) Kinds of mutations
c) Spontaneous mutation
d) Artificial mutagenesis and antimutagenesis
e) Why do genotypes mutate?
5. Struggle for fidelity
a) Two mechanisms of fidelity in DNA replication
b) Cleaning up after DNA replication
c) Undoing damages carefully
d) Mechanisms and patterns of mutation
e) Broken maintenance
6. Mutation rates
a) Sequencing mother-father-offspring trios
b) Genotype-level data on mutation rates
c) Exceptionally high mutation rates
d) Rates of phenotypically drastic mutations
e) Rates of mutations affecting complex traits
7. Guilty old males
a) Guilty older parents
b) Guilty males
c) Slow and fast evolution of sex chromosomes
d) Conclusive evidence
e) Selection between cells
8. Natural selection
a) Vulnerable adaptations and their evolutionary origin
b) Two basic characteristics of selection
c) Data on fitnesses of phenotypes
d) Positive, negative, and balancing selection
e) Strength of selection at a locus
9. Meaningful DNA and junk DNA
a) Selective neutrality and random drift
b) Effective population size
c) Junk DNA provides the simplest evidence for evolution
d) Finding meaningful genome segments
e) The genomic rate of deleterious mutations
10. It takes all the running you can do
a) Middle class neighborhood for Drosophila
b) Selection on a quantitative trait
c) Mutation-selection equilibrium
d) Inbreeding depression
e) When selection is powerless
11. Imperfection of genotypes and phenotypes
a) Quality, perfection, and imperfection
b) Five evolutionary causes of imperfection
c) Weakly prefect human genotype and phenotype
d) Native, novel, and perfect environments
e) Factors, exacerbating mutational imperfection
12. Our lousy genotypes
a) Properties of a deleterious allele
b) Human deleterious alleles and de novo mutations
c) Imperfection of human genotypes
d) Variation of human genotypes
e) Selection in human populations
13. Our lousy phenotypes
a) Brain, our most vulnerable organ
b) Imperfection of human phenotypes
c) Variation of human phenotypes
d) Effects of heredity on human phenotypes
e) Deleterious alleles affecting human phenotypes
14. Mutational pressure on human phenotypes
a) Persisting alleles and de novo mutations
b) The concept of mutational pressure
c) de novo mutations and diseases
d) de novo mutations and quantitative traits
e) de novo mutations and longevity
15. Our future
a) How much selection is still going on?
b) Will the mutational pressures remain constant?
c) Optimistic and pessimistic scenarios
d) Mutationless utopia
e) Anticipated progress in the next 20 years
16. What to do?
a) Ethical prohibitions
b) Lessons from history
c) What about doing nothing?
d) Two fantastic options
e) Can artificial selection of humans be acceptable?
f) Is genomic testing for me?
g) Should I freeze my sperm?
h) Conclusions
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Biography
Alexey S. Kondrashov, PhD is Professor of Ecology and Evolutionary Biology at the University of Michigan, Ann Arbor. His research interests include evolution of sex and genetic recombination, properties of spontaneous deleterious mutations and of selection against them, and dynamics of genetic variation in natural and artificial populations.
