A Short History of Genetics

[2020-09-07]

From creationists to evolutionists:

The creationists’ explanation of the observed biological variation, although still present to this day, has been superseded by the evidence-based evolutionists’ view that some common ancestors preceded present-day life-forms.

From Larmarckian to Darwinian evolution:

Among the evolutionary theories in the 19th century, the Lamarckian evolution of heritable somatic variations in response to the environment, was the most attractive even decades after Darwin published his book “On the origin of species by natural selection or the preservation of favoured races in the struggle for life”1. However, after years of genetics research, the Lamarckian view as the general phenomenon to explain evolution was eventually superseded by Darwin’s theory of evolution through natural selection.2 Darwin recognised the stochastic nature of heritable variation on which selection acts on in a continuous and gradual manner.

From Biometricians and Mendelians to a unified theory of evolution grounded on the theory of inheritance:

Biometricians were firm believers and advocates of continuous evolution, i.e. selection acts on many loci with small effects. They supported Darwin’s theory of gradual continuous evolutionary change.3 On the other hand, Mendelians were advocates of discontinuous or discrete evolution, i.e. selection acts on a few loci with large effects. This support for discontinuous evolution predates the rediscovery of Mendel’s theory of inheritance4 in 1900, and traces back to Huxley and Galton who themselves were the earliest supporters and admirers of Darwin.3 In 1918, Fisher merged these two schools of thought with his paper “The Correlation between Relatives on the supposition of Mendelian Inheritance”5. He rigorously demonstrated that Mendelism and Darwinian selection on small continuous variation were complementary. This was followed by the corroboration of the works of Haldane in his 1924 paper (A Mathematical Theory of Natural and Artificial Selection-I)6, and culminating with Wrights’ 1931 paper on “Evolution in Mendelian populations”2. These works have laid the Mendelian basis of quantitative variation and the mutation-selection model of evolution.

From “classical” to “balance” view of variability:

By the middle of the 20th century, the theoretical body of knowledge on population genetics stemming from Fisher, Wright and Haldane continued to expand together with the growing empirical data on fitness, and other quantitative traits, as well as chromosomal and biochemical polymorphisms.7 The 1950’s saw the debate between the “classical” view of variability and the “balance” view of variability, where Muller and Dobzhansky, respectively were the most well known proponents of.7 The classical view postulates that functional wild type alleles dominate populations and deleterious mutant alleles are at low frequencies; while the balance view posits that many genes have multiple functional alternative alleles maintained at intermediate frequencies by balancing selection. Before nucleotide sequencing, electrophoretic variants, i.e. proteins with varying mobility on agarose gel under an electric field, were shown to be abundant and the balance view was thought to have prevailed. However, Lewontin and Hubby (1966) pointed out that this does not necessarily imply balancing selection, it can also be indicative of neutral or nearly neutral variants8.

Selectionists and neutralists:

Wright in the 1930s recognised the importance of genetic drift in shaping the genetic variation of populations2,9, but it was set-aside in favour of the “selectionist” view of the predominance of loci under selective forces. The 1960s to 1980s saw the resurgence of the “neutralist” view, which posits that most of the molecular variation is neutral or nearly neutral such that the difference between and within species are under the control of drift and mutation rather than selection10–13. The utility of the neutralist view was demonstrated by Kimura in 1968 with his use of the “molecular clock” derived from the finding that the rate of neutral sequence substitution between species is equivalent to neutral mutation rate10. The neutral theory of evolution was rigorously formulated by Kimura and Ohta in the early 1970s14,15. The first methods of interrogating nucleotide sequence variation developed in the 1970s, were instrumental in revealing the abundance of neutral variants and the rarity of nonsynonymous nucleotide variation in Drosophila16,17. This was confirmed in 1983 by the ground-breaking work of Kreitman using the Maxam–Gilbert technique (differential purine-pyrimidine cleavage) to sequence 11 copies of Adh locus of Drosophila melanogaster.18 Powerful tests to study population genetics in empirical populations were developed which tests departures from neutrality, stemming from Ewen’s concept of the scaled mutation rate =4Ne, where Ne is the effective population size and μ is the mutation rate. Watterson, Nei and Tajima developed methods to estimate this parameter and applied them on empirical sequence data.19–23 The neutral theory opened the door for better appreciation of the role of drift on real-world populations with finite population sizes12, which is especially true in ecology when dealing with endangered species, where effective population sizes are severely limited. From the backdrop of neutral theory came the coalescent theory24. It simplified the analysis of neutral sequence variation by generating backward simulations instead of forward simulations, with subsequent developments incorporating effects of linkage disequilibrium (LD), selection, migration, and other demographic factors.25 To this date, neutral theory has not been without opposition. Gillespie argued that the effects of neutral evolution can alternatively be explained by models of selection in spatially and temporally variable environments.26 Kern and Hahn in 2018 have concluded that a large body of genomic sequence evidence to-date rejects the neutral theory since genomes appear to be largely shaped directly and indirectly by selective forces.11 But Jensen et al in 2019 heavily criticised the narrow definition of neutral theory and the weak and flawed empirical evidence presented by Kern and Hahn (2018). They argue that current empirical evidence are straight-forward extensions of Kimura’s neutral theory, demonstrating its continued importance rather than rejecting it.12

From variance partitioning to QTL mapping, genome-wide association and genomic prediction:

Parallel to the developments in population genetics is the rapid advancement of quantitative genetics. Galton, Weldon and Pearson were the pioneers of quantitative genetics prior to Fisher’s synthesis.3,27 Fisher’s 1918 paper “The Correlation between Relatives on the supposition of Mendelian Inheritance”5 is not only the landmark paper which established evolution in the light of Mendelian genetics but it is also the seminal paper on modern quantitative genetics. Fisher, together with Wright and Haldance developed much of the theoretical basis of quantitative genetics. Prior to genotyping technologies which characterise genomic variants, the classical approaches to quantitative genetics analysis were to estimate the number of loci controlling the trait28, and to perform variance components analysis to estimate heritability. Total phenotypic variance can be partitioned into its various genetic, environmental at residual components by exploiting the relationships between parents, offsprings, and siblings usually generated from artificial crosses in plants and animals.29,30 Linkage disequlibrium (LD) mapping mapping, first performed by Sturtevant in 1913 on the 6 sex-linked qualitative traits of Drosophila31, was the precursor to quantitative trait loci (QTL) mapping using genome-wide markers. The advent of affordable high-throughput genotyping technologies paved the way for the elucidation of the genetic basis of quantitative traits using QTL mapping and genome-wide association studies (GWAS). QTL mapping exploits the variation derived from synthetic crosses, i.e. biparental populations, and multi-parental population, to detect major QTL controlling quantitative traits.32 GWAS, on the other hand, uses the natural variation found in wild and domesticated populations, and even advanced generational synthetic populations. Tanaka’s group in 2002 reported the first genome-wide association study, where they identified a candidate locus associated with susceptibility to myocardial infarction in humans33,34. Despite having resolved the problem of missing heritability by recognising the small effects of numerous loci below stringent significance thresholds35–37, our understanding of the genetic basis of quantitative traits remains largely incomplete.38–40 In response to this, an “omnigenic” view of complex traits was put forward in 2017. This view posits that since association signals for most complex traits are spread across the genome and unbiased towards known genes, then the gene regulatory networks controlling the trait must be sufficiently interconnected such that most of the heritability can be explained by mechanisms outside the core pathways.40 Propelled by the same revolution in genotyping technologies as GWAS, predicting quantitative traits without the need to perform significance tests, i.e. genomic prediction (GP) or genomic selection, was conceived. In 2001, Meuwissen, Hayes and Goddard in response to the inefficient use of dense genomic data in QTL mapping experiments, proposed an approach which circumvents candidate loci detection to directly predict genotypic values using genome-wide marker data41. In contrast to QTL mapping and GWAS, GP aims to simply predict quantitative traits without the need to further identify and characterise the genes and molecular mechanisms involved in the expression of the phenotype.

Chromosome theory of inheritance, DNA, restriction endonucleases, polymerase chain reaction and genome sequencing:

Inextricably intertwined with the developments in population and quantitative genetics, are the technological advancements in genotyping. These have enabled the interrogation of the genetic basis of traits and the evolutionary forces acting on populations. In the early 20th century, Sutton and Boveri independently developed the chromosome theory of inheritance42,43. Not long after, Morgan and Sturtevant provided evidence for this theory by demonstrating the role of chromosomes in carrying the heritable genetic material in Drosophila.31,44 Hämmerling in 1943, as well as Avery, MacLeod and McCarthy in 1944 established deoxyribonucleic acid (DNA) as the molecular basis of inheritance.45,46 In 1953, Watson, Crick, Wilkins and Franklin discovered the structure of DNA.47 The potential of restriction endonucleases in genotyping specifically for determining nucleotide sequence was first recognised by Dana and Nathans in 1971.48 In 1976, DNA polymerase from Thermus aquaticus was discovered and described.49 In 1977, Sanger, Nicklen and Coulson developed the first method of sequencing nucleotides.50 In 1987, Mullis and Faloona developed the now ubiquitous polymerase chain reaction (PCR).51 By the 1980s, genome-wide sequencing was still financially prohibitive because of low throughput. Several molecular markers were developed that relied on the polymorphisms revealed by digesting DNA with different endonucleases and by PCR amplification of different regions of the genome. Restriction fragment length polymorphisms (RFLP) based on the differential cut sites generated by restriction endonucleases were the first nucleotide-based molecular markers developed.52 This was followed by the random amplified polymorphic DNA (RAPD) markers which used arbitrary primers in PCR to amplify a set of fragments.53,54 Amplified fragment length polymorphisms (AFLP) combined restriction enzyme digestion and PCR.55 Simple sequence repeat (SSR) markers are PCR-amplified highly repetitive elements in all eukaryotic genomes.56,57 Incremental improvements to Sanger sequencing were made through this period including the replacement of radiolabelling with fluorometric-based detection and the use of capillary based electrophoresis.58 The advent of the next generation of sequencing (NGS) technologies in the 21st century saw a huge leap in throughput. These NGS platforms can be divided into 3 categories: those which perform sequencing-by-synthesis (SBS), sequencing-by-ligation (SBL), and single-molecule sequencing (SMS).59 SBS platforms were the first to be commercially available. These include 454 Roche pyro-sequencing introduced in 2004, Solexa 1G (Illumina) in 2006, and Ion Torrent in 2010. ABI SOLiD introduced in 2007 is the only SBL platform. SMS platforms include Pacific Biosciences SMRT introduced in 2010 and Oxford Nanopore MinION in 2014. These NGS platforms together with the development of sophisticated bioinformatics frameworks have democratised genomic and transcriptomic characterisation.

An in-depth analysis of the history until the 1970s was provided by Provine in his book “The origins of theoretical population genetics”3. A continuation of this history was provided by Charlesworth and Charlesworth in their review entitled “Population genetics from 1966 to 2016”7. Various other historical accounts and reviews are mentioned below.

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