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2/3/2015
Copy number variation – Concept and consequences
Copy number variation in livestock and
companion animals
A window to domestication
and other evolutionary processes
• Copy number variation (CNV) can be defined as genomic duplications or
deletions, with sizes between 50 bp and several Mb, that are polymorphic
amongst individuals of a given species.
• CNVs can have effects on phenotypes by altering the expression or the
structure of transcripts encoded by genes located within or nearby them.
• Studies carried out in Drosophila suggest that 21% of genes contained
within CNVs have an increased expression variance, but probably this
figure is much larger (Zhou et al. 2011).
Marcel Amills
Center for Research in Agricultural Genomics
Copy number variation modifies expression time courses
Chaignat et al. (2011) Genome Res. 21: 106–113.
The Neolithic revolution and domestication
Domestication involved changes in animal
behavior and aspect
ASPECT
-Reduced brain size.
-Piebald coloration.
-Snout shortening
-Decrease in molar length
Demography and drift
Artificial selection
PHYSIOLOGY
-Earlier sexual maturity
BEHAVIOR
-Less territorial and aggressive
-Reduced fear to humans.
-Increased tolerance to stress.
-Reduced wariness
Dong et al. 2014. Annu. Rev.
Anim. Biosci. 2:65–84
• Domestication may be understood as a mutualistic long-term relationship between
humans and plant or animal species that involves a selective advantage for both
partners.
• Domestication can be interpreted as an ongoing process.
Many human and mouse neurodevelopmental
pathologies are produced by CNVs
Part of these changes may have
been produced by CNVs
A comparison of CNV distribution in wild boars and pigs
Paudel et al. (2013) BMC Genomics 14: 449
• European (N=3) and Asian (N=3) wild boar plus 10 domestic pigs are
sequenced x7-x10, leading to the discovery of 3,118 CNV with an average
size of 13 kb.
• CNVRs contain 545 genes
Functional enrichment:
- Sensory perception of smell
- Neurological function
- Signal transduction
- Metabolism
Homozygous genotypes for the 15q11.2 deletion: higher risk of schizophrenia
• The large majority of CNVR are shared between wild boar and domestic pigs.
Heterozygous genotypes: diffficulties in learning mathematics and reading
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A comparison of CNV distribution in wild boars and pigs
Similar distribution of CNVs in dogs and wolves
Ramírez et al. (2014) BMC Genomics 15: 465
Rubin et al. (2012) PNAS 14: 449
• Sequencing of pig and wild boar pools reveals a large number of copy number
variants.
• The comparison of CNV distribution in dogs
and wild canids shows that:
- around 50% are shared
• However, only five of them show positional concordance with candidate selective
sweep regions showing an excess of homozygosity.
- approximately 12% are dog-specific
• No gene-ontology category is overrepresented
in the dog-specific CNV regions.
• Identification of 25 CNVR with highest VST
between dogs and wolves (in red).
• Six genes involved in neurological function (EML5,
ZNF500, SLC6A11, ELAVL2, RGS7, TOP3B).
• SLC6A11: related with schizophrenia and autism.
Behavioral traits have a complex genetic architecture
Glove test for measuring aggressivity in rats
(Albert et al. 2009. Genetics 182: 541)
Artificial selection created an enormous amount of
phenotypic diversity in domestic animals
Chromosome distribution of significant anxietyrelated LOD scores across the mouse genome
(Saffron et al. 2006. Eur J Human Genet 14: 721)
• F2 mouse intercross from two lines selected for high aggressivity and tameness
(Heyne et al. 2014). An approach that assumes that causative mutations are
segregating within lines identifies 4 times more loci than another one assuming
fixation.
• Identification of two additive QTL that explain 7% of tameness variance in rats
plus an epistatic network of five loci that explain 14% of it (Albert et al. 2009).
• Studies performed in Drosophila also suggest a polygenic basis for behavioral
traits combined with extensive pleiotropy and epistasis (Mackay et al. 2008).
Practical reasons for selecting color
• In the world, there are around 300-400 pig breeds with different coat colors,
shapes and production performances. All of them, descend from the wild boar.
• Coat color has been selected by humans from immemorial times.
• The genetic determinism of coat color is much simpler than that of behavior
Religious and cultural reasons for selecting color
White pigs are much easier to spot than their wild ancestors.
"Speak unto the children of Israel, that they
bring thee a red heifer without spot, wherein
is no blemish (Numbers 19:2).
White wool can be dyed more easily
than the colored one.
Tallensi tribe from Ghana
Sizes and colors of sacrificed animals
have different meanings and values
In traditional Chinese mythology, the colour black is
associated with water.
"In a supplication rite for rains, we should use black
sheep, and there will then be heavy rain"
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White color in pigs is associated with the
duplication of the KIT gene
White color in sheep is associated with the
duplication of the ASIP gene
Rubin et al. (2012) PNAS 14: 449
• Normal KIT signaling is required for development and survival of neural crest-derived
melanoblasts.
• The agouti signaling protein stimulates the synthesis of pheomelanin (yellow).
• Dominant white is associated with a 450-kb duplication (DUP1) encompassing the
entire KIT gene and a splice mutation causing exon skipping (Giuffra et al. 2002).
• A 190 kb tandem duplication of the ASIP gene is associated with a white coat
in sheep (Norris et al. 2008. Genome Res. 18: 1282)
• Patch has only the 450-kb duplication, while Belt is associated with a duplication
100 kb upstream the KIT gene (DUP2, regulatory role?).
• The duplicated copy is regulated by an ITCH promoter and shows an ubiquitous
pattern of expression.
Comb shape in chicken is determined by copy
number variation
Pea comb in chicken is determined by a CNV
mapping to the SOX5 gene
Wright et al. (2009) PLoS Genet 5: e1000512
ROSE
COMB
PEA
COMB
qPCR analysis of the SOX5 CNV
Normal (green) and ectopic (red) expression of
SOX5 in pea-comb chicken
WALNUT
• A CNV at intron 1 of the SOX5 gene is associated with the pea comb phenotype.
• Blood circulation through the comb and wattles helps to dissipate body heat.
• Mutant combs could represent an adaptation to cold climates (diminish heat
loss and avoid frostbite).
• Immunostaining shows an ectopic expression of SOX5 in the embryonic ectodermal
region that yields comb and wattles.
Adaptation to a starch-rich diet in dogs
Conclusions
• The majority of studies performed in domestic species have revealed that
CNVs are enriched in genes influencing neural development.
Axelsson et al. (2013)
Nature 495:360
Freedman et al. (2014)
PLoS Genet 10: e1004016
• Little success in establishing functional links between CNV and behavioral
traits of key importance during the process of domestication.
• Causal relationships between CNV and Mendelian aspect-related traits
selected during or after domestication.
• Future developments:
• Copy number variation of the AMY2B gene in dogs and wolves, with a
very substantial increase in the former.
- Dissecting behavior through GWAS/sequencing approaches in
wild x domestic crosses or in divergently selected domestic lines.
- Paleogenomics: characterizing genetic variation of ancient specimens.
• Low copy number in dog breeds (Dingo and Husky) not linked to agrarian
societies.
- Technical improvements: Quality of reference genomes, creation of
CNV databases, better genome annotation etc.
• Increased amylase activity might represent an ancient adaptation to
feeding on agricultural refuse.
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