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"Andersson, Leif"
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Molecular genetic variation of animals and plants under domestication
Domesticated plants and animals played crucial roles as models for evolutionary change by means of natural selection and for establishing the rules of inheritance, originally proposed by Charles Darwin and Gregor Mendel, respectively. Here, we review progress that has been made during the last 35 y in unraveling the molecular genetic variation underlying the stunning phenotypic diversity in crops and domesticated animals that inspired Mendel and Darwin. We notice that numerous domestication genes, crucial for the domestication process, have been identified in plants, whereas animal domestication appears to have a polygenic background with no obvious “domestication genes” involved. Although model organisms, such as Drosophila and Arabidopsis, have replaced domesticated species as models for basic research, the latter are still outstanding models for evolutionary research because phenotypic change in these species represents an evolutionary process over thousands of years. A consequence of this is that some alleles contributing to phenotypic diversity have evolved by accumulating multiple changes in the same gene. The continued molecular characterization of crops and farm animals with ever sharper tools is essential for future food security.
Journal Article
White horses – non-coding sequences drive premature hair greying and predisposition to melanoma
The Grey allele in horses is causing premature hair greying and susceptibility to melanoma. The causal mutation is a 4.6 kb tandem duplication in intron 6 of the Syntaxin 17 gene. A recent study demonstrated that the most common allele at the Grey locus (G3) involves three tandem copies of this sequence, whilst a more rare allele (G2) has two tandem copies and the wild-type allele (G1) only one copy. The G3 allele is causing fast greying and high incidence of skin melanoma, whereas the G2 allele is causing slow greying and no obvious increase in melanoma incidence. Further somatic copy number expansion has been documented in melanoma tissue from Grey horses. Functional studies showed that this intronic sequence acts as a weak melanocyte-specific enhancer that becomes substantially stronger by the copy number expansion. The Grey mutation is associated with upregulated expression of both Syntaxin 17 and the neighbouring NR4A3 gene in Grey horse melanomas. It is still an open question which of these genes is most important for the phenotypic effects or if causality is due to the combined effect of upregulation of both genes. Interestingly, RNAseq data in the Human Protein Atlas give support for a possible role of NR4A3 because it is particularly upregulated in human skin cancer, and it belongs to a cluster of genes associated with skin cancer and melanin biosynthesis. The Grey mutation and its association with melanoma provide a possibility to study the path to tumour development in numerous Grey horses carrying exactly the same predisposing mutation.
Journal Article
Prevalence of cancer in relation to signs of periodontal inflammation
We investigated the associations between periodontal inflammation (gingivitis and periodontitis) and all-kind malignancies, specifically breast and prostate cancer, in a cohort followed-up for 30 years. The study hypothesis was based on the oral inflammation vs . systemic health paradigm. A sample of 2,168 subjects from an original cohort of 105,718 individuals from the greater Stockholm area in Sweden that had been followed since 1985 was investigated. Swedish national health registers were used in the study. Chi-square tests and logistic multiple regression analyses were conducted. The results showed that periodontitis was significantly associated with any cancer after adjusting for gender, age, income, and education (p = 0.015). The probability of getting cancer increased on average by 38% if the patient had periodontitis vs . had not; the odds ratio was 1.380 (95% confidence interval l.066-1.786). No significant association was observed between periodontitis and breast cancer (p = 0.608), while the association between periodontitis and prostate cancer tended towards significance (p = 0.082). However, no statistically significant difference was found between the observed and the calculated distribution of any cancer in gingivitis groups (p = 0.079). Thus, the study hypothesis was partly confirmed by showing a statistically significant association between periodontitis and any cancer.
Journal Article
Rapid hybrid speciation in Darwin’s finches
Galapagos finches have driven hypotheses of how speciation occurs. Most commonly, it is assumed that natural selection separates species originating from a single population on the basis of variation in traits that confer advantages for survival and reproduction. Lamichhaney et al. document a case where cross-species hybridization established a reproductively isolated lineage, which demonstrates a process known as homoploid hybrid speciation in action (see the Perspective by Wagner). The authors used genetic markers and phenotypic analyses to create a pedigree that revealed how a cross-island migrant bred with a native species to form a self-perpetuating hybrid population that was reproductively isolated from both parental species. Science , this issue p. 224 ; see also p. 157 Homoploid hybrid speciation in Galapagos finches results in reproductive isolation after only three generations. Homoploid hybrid speciation in animals has been inferred frequently from patterns of variation, but few examples have withstood critical scrutiny. Here we report a directly documented example, from its origin to reproductive isolation. An immigrant Darwin’s finch to Daphne Major in the Galápagos archipelago initiated a new genetic lineage by breeding with a resident finch ( Geospiza fortis ). Genome sequencing of the immigrant identified it as a G. conirostris male that originated on Española >100 kilometers from Daphne Major. From the second generation onward, the lineage bred endogamously and, despite intense inbreeding, was ecologically successful and showed transgressive segregation of bill morphology. This example shows that reproductive isolation, which typically develops over hundreds of generations, can be established in only three.
Journal Article
Population genomic analysis identifies the complex structural variation at the fibromelanosis (FM) locus in chicken
Phenotypic diversity and its genetic basis are central questions in biology, with domesticated animals offering valuable insights due to their rapid evolution the last 10,000 years. In chickens, fibromelanosis (FM) is a striking pigmentation phenotype characterized by hyperpigmentation. A previous study identified a complex structural variant involving both two large duplications (127.4 and 170.5 kb in size) and inversions associated with upregulated expression of the
Endothelin 3
(
EDN3
) gene. However, the detailed organization of the structural arrangements have remained unclear. In this study, we conducted a comprehensive genomic survey of 517 FM chickens representing 44 different populations. Our results elucidate the complex arrangement of the duplications and inversions at the
FM
locus based on the large-scale genomic survey, population level genotyping, and linkage disequilibrium analysis, providing conclusive support for one specific configuration of the two large duplications, resolving a controversy that has been unresolved for more than a decade. Our results show that the birth of this complex structural variant must have involved an interchromosomal rearrangement creating fixed heterozygosity due to sequence differences between the two copies of the 127.4 kb duplication. This study shows how population genomics can be used to understand complex structural variations that underlie phenotypic variation.
Journal Article
Asymmetric introgression reveals the genetic architecture of a plumage trait
Genome-wide variation in introgression rates across hybrid zones offers a powerful opportunity for studying population differentiation. One poorly understood pattern of introgression is the geographic displacement of a trait implicated in lineage divergence from genome-wide population boundaries. While difficult to interpret, this pattern can facilitate the dissection of trait genetic architecture because traits become uncoupled from their ancestral genomic background. We studied an example of trait displacement generated by the introgression of head plumage coloration from personata to alba subspecies of the white wagtail. A previous study of their hybrid zone in Siberia revealed that the geographic transition in this sexual signal that mediates assortative mating was offset from other traits and genetic markers. Here we show that head plumage is associated with two small genetic regions. Despite having a simple genetic architecture, head plumage inheritance is consistent with partial dominance and epistasis, which could contribute to its asymmetric introgression.
Hybrid zones are windows into the evolutionary process. Semenov et al. find that the head plumage differences between white wagtail subspecies have a simple genetic basis involving two small genetic regions, in which partially dominant and epistatic interactions help to explain how this sexual signal has become decoupled from other plumage traits.
Journal Article
Genome-wide association analysis in domestic animals: a powerful approach for genetic dissection of trait loci
Domestic animals have a sufficiently old history (thousands of generations) to allow evolution of phenotypes, but also a sufficiently young history (~10,000 years) to allow powerful genetic dissection of phenotypic diversity. Domestic animals are therefore a unique resource for exploring genotype-phenotype relationships. Quantitative Trait Locus (QTL) mapping has been very successful in domestic animals but the identification of Quantitative Trait Mutations (QTMs) has been hard although a few prominent success histories have been reported. Genome-wide association analysis is now emerging as a powerful method for high-resolution mapping of loci controlling phenotypic traits in domestic animals. In two recent proof-of-principle studies we have used this approach to identify the mutations underlying two monogenic trait loci in dogs, white spotting and the hair ridge in Ridgeback dogs. In each case, we used only about 10 cases and 10 controls and mapped the locus to a region of about one mega base pair. In both cases the underlying mutations were non-coding underscoring the significance of regulatory mutations as a source for phenotypic diversity. Furthermore, we were able to shed light on the evolution of the allelic series at the white spotting (S) locus in dogs which encodes the microphthalmia-associated transcription factor (MITF). Our data showed that the three variant alleles described at this locus (Irish spotting, piebald and extreme white) do not represent three independent mutations but rather different combinations of a set of regulatory mutations affecting MITF expression. This is an excellent illustration of how the characterization of alleles selected during animal domestication contributes to an improved understanding of genotype-phenotype relationships.
Journal Article
Ornithine decarboxylase antizyme inhibitor 2 (AZIN2) is a signature of secretory phenotype and independent predictor of adverse prognosis in colorectal cancer
Ornithine decarboxylase (ODC) is the rate-limiting enzyme of polyamine synthesis. The two ODC antizyme inhibitors (AZIN1) and (AZIN2) are regulators of the catalytic activity of ODC. While AZIN1 is a regulator of cell proliferation, AZIN2 is involved in intracellular vesicle transport and secretion. There are no previous reports on the impact of AZIN2 expression in human cancer. We applied immunohistochemistry with antibodies to human AZIN2 on tissue micro- arrays of colorectal cancers (CRC) from 840 patients with a median follow-up of 5.1 years (range 0-25.8). The 5-year disease-specific survival rate was 58.9% (95% Cl 55.0-62.8%). High AZIN2 expression was associated with mucinous histology (p = 0.002) and location in the right hemicolon (p = 0.021). We found no association with age, gender, stage, or histological tumor grade. High tumor expression of AZIN2 predicted an unfavorable prognosis (p<0.0001, log-rank test), compared to low AZIN2 expression. Cox multivariable analysis identified AZIN2 as an independent factor of an unfavorable prognosis in CRC. The strongest AZIN2 expression was seen in invasive tumor cells having morphological features of epithelial-mesenchymal transition (EMT). Induction of EMT in HT-29 CRC cells lead to upregulated expression of endogenous AZIN2. Given that AZIN2 is a regulator of vesicle transport and secretion, we overexpressed human AZIN2 cDNA in T84 CRC cells, and found strongly enhanced accumulation of CD63-positive exosomes in the culture medium. These findings indicate that AZIN2 expression is a signature of EMT-associated secretory phenotype that is linked to an adverse prognosis in CRC.
Journal Article
ZBED6 regulates Igf2 expression partially through its regulation of miR483 expression
The expression of
Igf2
in mammals shows a complex regulation involving multiple promoters and epigenetic mechanisms. We previously identified a novel regulatory mechanism based on the interaction between the transcriptional factor ZBED6 and
Igf2
intron. Disruption of the ZBED6-
Igf2
interaction leads to a dramatic up-regulation of IGF2 expression postnatally. In the current study we characterize an additional layer of regulation involving
miR483
encoded by another
Igf2
intron. We found a highly significant up-regulation of
miR483
expression when the ZBED6-
Igf2
axis is disrupted in transgenic mice. Furthermore, CRISPR/Cas9 mediated knock-out of
miR483
in C2C12 myoblast cells, both wild-type and cells with disrupted ZBED6-
Igf2
axis (
Igf2
dGGCT
), resulted in down-regulation of
Igf2
expression and a reduced proliferation rate. This was further validated using
miR483
mimics and inhibitors. RNA-seq analysis revealed a significant enrichment of genes involved in the PI3K-Akt signaling pathway among genes down-regulated in
miR483
−/−
cells, including
Igf2
down-regulation. The opposite pattern was observed in
Igf2
dGGCT
cells, where
Igf2
is up-regulated. Our data suggest a positive feedback between
miR483
and
Igf2
promoter activity, strongly affecting how ZBED6 controls
Igf2
expression in various cell types.
Journal Article