Applications of Population Genetics to Animal Breeding,from Wright,Fisher and Lush to Genomic Prediction

Although animal breeding was practiced long before the science of genetics and the relevant disciplines of population and quantitative genetics were known, breeding programs have mainly relied on simply selecting and mating the best individuals on their own or relatives’ performance. This is based on sound quantitative genetic principles, developed and expounded by Lush, who attributed much of his understanding to Wright, and formalized in Fisher’s infinitesimal model. Analysis at the level of individual loci and gene frequency distributions has had relatively little impact. Now with access to genomic data, a revolution in which molecular information is being used to enhance response with “genomic selection” is occurring. The predictions of breeding value still utilize multiple loci throughout the genome and, indeed, are largely compatible with additive and specifically infinitesimal model assumptions. I discuss some of the history and genetic issues as applied to the science of livestock improvement, which has had and continues to have major spin-offs into ideas and applications in other areas.THE success of breeders in effecting immense changes in domesticated animals and plants greatly influenced Darwin’s insight into the power of selection and implications to evolution by natural selection. Following the Mendelian rediscovery, attempts were soon made to accommodate within the particulate Mendelian framework the continuous nature of many traits and the observation by Galton (1889) of a linear regression of an individual’s height on that of a relative, with the slope dependent on degree of relationship. A polygenic Mendelian model was first proposed by Yule (1902) (see Provine 1971; Hill 1984). After input from Pearson, Yule again, and Weinberg (who developed the theory a long way but whose work was ignored), its first full exposition in modern terms was by Ronald A. Fisher (1918) (biography by Box 1978). His analysis of variance partitioned the genotypic variance into additive, dominance and epistatic components. Sewall Wright (biography by Provine 1986) had by then developed the path coefficient method and subsequently (Wright 1921) showed how to compute inbreeding and relationship coefficients and their consequent effects on genetic variation of additive traits. His approach to relationship in terms of the correlation of uniting gametes may be less intuitive at the individual locus level than Malécot’s (1948) subsequent treatment in terms of identity by descent, but it transfers directly to the correlation of relatives for quantitative traits with additive effects.From these basic findings, the science of animal breeding was largely developed and expounded by Jay L. Lush (1896–1982) (see also commentaries by Chapman 1987 and Ollivier 2008). He was from a farming family and became interested in genetics as an undergraduate at Kansas State. Although his master’s degree was in genetics, his subsequent Ph.D. at the University of Wisconsin was in animal reproductive physiology. Following 8 years working in animal breeding at the University of Texas he went to Iowa State College (now University) in Ames in 1930. Wright was Lush’s hero: ‘I wish to acknowledge especially my indebtedness to Sewall Wright for many published and unpublished ideas upon which I have drawn, and for his friendly counsel” (Lush 1945, in the preface to his book Animal Breeding Plans). Lush commuted in 1931 to the University of Chicago to audit Sewall Wright’s course in statistical genetics and consult him. Speaking at the Poultry Breeders Roundtable in 1969: he said, “Those were by far the most fruitful 10 weeks I ever had.” (Chapman 1987, quoting A. E. Freeman). Lush was also exposed to and assimilated the work and ideas of R. A. Fisher, who lectured at Iowa State through the summers of 1931 and 1936 at the behest of G. W. Snedecor.Here I review Lush’s contributions and then discuss how animal breeding theory and methods have subsequently evolved. They have been based mainly on statistical methodology, supported to some extent by experiment and population genetic theory. Recently, the development of genomic methods and their integration into classical breeding theory has opened up ways to greatly enhance rates of genetic improvement. Lush focused on livestock improvement and spin-off into other areas was coincidental; but he had contact with corn breeders in Ames and beyond and made contributions to evolutionary biology and human genetics mainly through his developments in theory (e.g., Falconer 1965; Robertson 1966; Lande 1976, 1979; see also Hill and Kirkpatrick 2010). I make no attempt to be comprehensive, not least in choice of citations.     

Differential degradation for small heat shock proteins IbpA and IbpB is synchronized in Escherichia coli: Implications for their functional cooperation in substrate refolding

Small heat shock proteins (sHSPs), as a conserved family of ATP-independent molecular chaperones, are known to bind non-native substrate proteins and facilitate the substrate refolding in cooperation with ATP-dependent chaperones (e.g., DnaK and ClpB). However, how different sHSPs function in coordination is poorly understood. Here we report that IbpA and IbpB, the two sHSPs of Escherichia coli, are coordinated by synchronizing their differential in vivo degradation. Whereas the individually expressed IbpA and IbpB are respectively degraded slowly and rapidly in cells cultured under both heat shock and normal conditions, their simultaneous expression leads to a synchronized degradation at a moderate rate. Apparently, such synchronization is linked to their hetero-oligomerization and cooperation in binding substrate proteins. In addition, truncation of the flexible N- and C-terminal tails dramatically suppresses the IbpB degradation, and somehow accelerates the IbpA degradation. In view of these in vivo data, we propose that the synchronized degradation for IbpA and IbpB are crucial for their synergistic promoting effect on DnaK/ClpB-mediated substrate refolding, conceivably via the formation of IbpA–IbpB-substrate complexes. This scenario may be common for different sHSPs that interact with each other in cells.     

The reliability of observational approaches for detecting interspecific parasite interactions: comparison with experimental results

Interactions among coinfecting parasites have the potential to alter host susceptibility to infection, the progression of disease and the efficacy of disease control measures. It is therefore essential to be able to accurately infer the occurrence and direction of such interactions from parasitological data. Due to logistical constraints, perturbation experiments are rarely undertaken to directly detect interactions, therefore a variety of approaches are commonly used to infer them from patterns of parasite association in observational data. However, the reliability of these various approaches is not known. We assess the ability of a range of standard analytical approaches to detect known interactions between infections of nematodes and intestinal coccidia (Eimeria) in natural small-mammal populations, as revealed by experimental perturbations. We show that correlation-based approaches are highly unreliable, often predicting strong and highly significant associations between nematodes and Eimeria in the opposite direction to the underlying interaction. The most reliable methods involved longitudinal analyses, in which the nematode infection status of individuals at one month is related to the infection status by Eimeria the next month. Even then, however, we suggest these approaches are only viable for certain types of infections and datasets. Overall we suggest that, in the absence of experimental approaches, careful consideration be given to the choice of statistical approach when attempting to infer interspecific interactions from observational data.     

Improving the Applicability of Quantitative Ecological Risk Assessment Tools—Understanding Demand-Side Changes

Quantitative ecological risk assessment (ERA) methods are the tools of choice for many natural resource management agencies and practitioners. However, a number of researchers and practitioners have recently highlighted that the application of quantitative ERA tools has perhaps been somewhat limited and this has stimulated discussion on the limitations of these methods, considered to be supply-side limitations in this analysis. By contrast, it is argued here that the demand for risk assessment tools has also changed substantively and this also acts to limit the use of ERA approaches. In particular, demand has changed through an increasing expectation that quantitative ERA tools will be able to capture ecosystem-scale, and sometimes global-scale interactions to support ecosystem-based management approaches. Similarly, the burgeoning use of market-based policy instruments often underpinned by the allocation of private property rights to an increasing number of ecosystem goods and services has fundamentally changed many natural resource management issues into allocation conflicts between alternate rights-holders. These demand-side changes represent both an opportunity and a challenge for developers of quantitative ERA tools.     

Small‐angle scattering for structural biology—Expanding the frontier while avoiding the pitfalls

The last decade has seen a dramatic increase in the use of small‐angle scattering for the study of biological macromolecules in solution. The drive for more complete structural characterization of proteins and their interactions, coupled with the increasing availability of instrumentation and easy‐to‐use software for data analysis and interpretation, is expanding the utility of the technique beyond the domain of the biophysicist and into the realm of the protein scientist. However, the absence of publication standards and the ease with which 3D models can be calculated against the inherently 1D scattering data means that an understanding of sample quality, data quality, and modeling assumptions is essential to have confidence in the results. This review is intended to provide a road map through the small‐angle scattering experiment, while also providing a set of guidelines for the critical evaluation of scattering data. Examples of current best practice are given that also demonstrate the power of the technique to advance our understanding of protein structure and function.     

Paleoenvironment of Ankilitelo Cave (late Holocene, southwestern Madagascar): implications for the extinction of giant lemurs

Following human arrival, Madagascar suffered well-documented megafaunal extinctions and widespread deforestation. Although humans are widely considered to be the primary cause of the extinctions, the relative contributions of climate change and human activities to this ecological transformation remain uncertain. Reconstructing the habitats of the giant lemurs of Madagascar can provide key information for understanding the evolutionary mechanisms involved in their extinction. In this study, I present a faunal analysis of the subfossil assemblage from Ankilitelo Cave, southwestern Madagascar. This assemblage documents the latest known occurrence of five species of extinct giant lemur, in association with abundant well-preserved small mammal remains. I compared the small mammal fauna at Ankilitelo with 27 extant Malagasy mammal communities spanning the range of Madagascar's habitat types. Similarities in species composition between modern communities and Ankilitelo were assessed using cluster analysis. Ecological similarities were examined by assigning each species to dietary, locomotor, activity pattern, and body size categories. Multiple discriminant analysis was then used to classify Ankilitelo relative to modern habitat types in Madagascar, based on the ecological structure of the subfossil fauna. Results indicate that the habitat surrounding Ankilitelo during the late Holocene was similar to the succulent woodlands of modern southwestern Madagascar. This suggests that approximately 500 yr BP, these semi-arid habitats supported a subfossil lemur community that included the highly-suspensory Palaeopropithecus, and deliberate slow-climber Megaladapis, as well as Archaeolemur, Pachylemur, and Daubentonia robusta. In such environments, these giant lemurs would likely have been highly vulnerable to increasing human pressure in southwestern Madagascar.     

tsORFdb: Theoretical Small Open Reading Frames (ORFs) database and massProphet: Peptide Mass Fingerprinting (PMF) tool for unknown small functional ORFs

Peptide mass fingerprinting (PMF) has become one of the most widely used methods for rapid identification of proteins in proteomics research. Many peaks, however, remain unassigned after PMF analysis, partly because of post-translational modification and the limited scope of protein sequences. Almost all PMF tools employ only known or predicted protein sequences and do not include open reading frames (ORFs) in the genome, which eliminates the chance of finding novel functional peptides. Unlike most tools that search protein sequences from known coding sequences, the tool we developed uses a database for theoretical small ORFs (tsORFs) and a PMF application using a tsORFs database (tsORFdb). The tsORFdb is a database for ORFeome that encompasses all potential tsORFs derived from whole genome sequences as well as the predicted ones. The massProphet system tries to extend the search scope to include the ORFeome using the tsORFdb. The tsORFdb and massProphet should be useful for proteomics research to give information about unknown small ORFs as well as predicted and registered proteins.     

Metabolism of green tea catechins by the human small intestine

Numerous studies have shown that green tea polyphenols can be degraded in the colon, and there is abundant knowledge about the metabolites of these substances that appear in urine and plasma after green tea ingestion. However, there is very little information on the extent and nature of intestinal degradation of green tea catechins in humans. Therefore, the aim of this study was to examine in detail the microbial metabolism and chemical stability of these polyphenols in the small intestine using a well-established ex vivo model. For this purpose, fresh ileostomy fluids from two probands were incubated for 24 h under anaerobic conditions with (+)-catechin (C), (-)-epicatechin (EC), (-)-epicatechin 3-O-gallate (ECG), (-)-epigallocatechin (EGC), (-)-epigallocatchin 3-O-gallate (EGCG) and gallic acid (GA). After lyophilisation and extraction, metabolites were separated, identified and quantified by high performance liquid chromatography-photodiode array detection (HPLC-DAD) and HPLC-ESI-tandem mass spectrometry. Two metabolites of EC and C (3', 4', 5'-trihydroxyphenyl-γ-valerolactone and 3', 4'-dihydroxyphenyl-γ-valerolactone) were identified. In addition, 3', 4', 5'-trihydroxyphenyl-γ-valerolactone was detected as a metabolite of EGC, and (after 24-h incubation) pyrogallol as a degradation product of GA. Cleavage of the GA esters of EGCG and ECG was also observed, with variations dependent on the sources (probands) of the ileal fluids, which differed substantially microbiotically. The results provide new information about the degradation of green tea catechins in the gastrointestinal tract, notably that microbiota-dependent liberation of GA esters may occur before these compounds reach the colon.