This is a
topic that has been barely covered here before, but is surely of interest for
many of my readers especially since the 2015 article on the genetic studies
involved in the Tauros Project was published by Rewilding Europe. The reason
why I have covered neither the article nor the issue of genetic proximity here as
such is that it is a lot to write and explain, and I haven’t had the time
previously. However, this summer I have the time and inspiration to finally
cover this topic appropriately.
There are several ways in which domestic
cattle can be “close to their ancestor”, several ways how genetic proximity is
defined or measured, and what it implicates for “breeding-back”. However, as I
always admit, I myself am a layman in the field of genetics so please point me
to mistakes if I made some.
What was
especially striking when Rewilding Europe published their article on genetics
was the chart of Nei genetic distance of a number of cattle breeds to the
aurochs. The most obvious result is that there is seemingly no clear
correlation between a less-derived phenotype and “genetic proximity” (see down
below), which led some people to conclude that “genetics don’t matter”. But
genetics do matter of course: if you insert an aurochs’ genome into a Holstein
zygote, you get an aurochs. But why this discrepancy? To solve this question
and to find out what it means for “breeding-back”, we have to look at what
“genetic closeness” means in this case.
Nei distance analysis published here |
How genetic
closeness is usually measured
Of course
it would be best and most comprehensive to compare the full length of two
genomes against each other. However, as genomes are huge molecules with a lot
of information (in the case of cattle, the genome includes 3 billion base pairs
and 22.000 genes), this would be very effortful. And apart from that, only a
very small fraction of the whole genome codes for the defining differences
between closely related species, and an even smaller portion codes for
individual variation. So in order to make it easier, geneticists often rely on easily
identifiable, short DNA sequences such as marker genes, and haplotypes of the
mitochondrial genome or Y chromosomes. The advantage of molecular marker genes,
such as cytochrome c and others, is
that there is a constant average mutation rate per generation and that they are
barely effected by selection as they have minor influence on the individual
phenotypic variation, especially because many variations are neutral. This also
makes them useful for determining the time of splitting up between evolutionary
lines (“molecular clock”, the markers being used are called molecular
chronometers). While variations on the mitochondrial genome, Y chromosome and their
haplogroups as well as other marker genes are often used to determine the time
of divergence or degree of genetic proximity under the assumption of a constant
mutation rate and that they are barely affected by phenotypic selection, their
influence on the actual phenotype and thus the nature of the animals is
comparably minor. Mitochondrial genes mostly serve functions in the
mitochondria themselves, and there are only a few genes on the Y chromosome
that are actually relevant (lying on the sex-determining region of the
chromosome). Haplotypes (variations passed on by only one parental lineage) are
often used as an indicator of relatedness, but they actually are just an
accumulation of more or less neutral variation on haplotypes and their
influence on the organism as a whole is really minor. That is why the variation
on those markers usually studied are barely affected by selection, what makes
them in turn good markers. But their influence on the genetic architecture of
the animals is meagre. They can indicate relatedness, but do not guarantee that
the rest of the genome, especially those regions coding for the particular
differences between the taxa compared, will be similar too.
As an
example: let us assume that we take the genome of an ordinary Holstein-Frisian
and exchange all sequences of its marker genes, haplotypes and even the
complete mitochondrial genome with those sequences of an original aurochs and
let that embryo develop. The result will still be a Holstein-Frisian, because
the genetic material exchanged are mostly more or less neutral variations on
genes that have a minor influence on the individual variation within a species
or even between related species and not the regions that define the differences
between a Holstein-Frisian and an aurochs. A Holstein cow with aurochs
mitochondria would still be a Holstein cow in our perception, because the
influence of mitochondrial DNA of the organism as a whole is comparably small.
Furthermore, haplotypic variation does neither determine the identity of an
individual or a species.
Most of the
identity of an organism is defined by the nuclear genome. If you want to
determine truly influential differences between aurochs and cattle, you would
have to look there. Which is why the geneticists cited in the Rewilding Europe
article have had a look at nuclear autosomal SNPs (Single nucleotid
polymorphisms). SNPs, as long as they lie on coding regions, do have an
influence on the phenotype. Many mutations causing cancer in humans, for
example, are SNPs. For the study, 770.000 SNPs have been investigated and
compared between one aurochs individual and 35 cattle breeds. They calculated
the Nei genetic distance and presented the results (shown above).
The genetic
difference between wild aurochs and domestic cattle
As far as
my understanding goes, the last word is surely not spoken with that. It is of
course state of the art to measure genetic distance using SNPS, haplotypes,
marker genes et cetera, but we have again to look at the relevant genetic
differences between aurochs and cattle. Just as the aurochs was neither defined
via its mitochondria or haplogroups, it also was not defined by a couple of
thousand SNPs. I imagine that the truly vital genetic differences between an
aurochs and domestic cattle concern the following biological aspects:
- neurology
-
endocrinology
-
developmental regulation: timing et cetera
- sexual
dimorphism
-
metabolism
-
morphologic aspects
-
immunology
As outlined
in a number of previous posts where you also find relevant literature (here and
here), a lot of the differences between domestic and wild morphology are
probably caused by pleiotropic effects and developmental cascades and therefore
concern the upper five points; probably only a few novel morphological
mutations appeared (alleles such as those causing scurred horns, new colour
variants, extreme cases of dachshund-leggedness etc.).
I think
those seven aspects are where we should look for the defining genetic
differences between cattle and Eurasian aurochs that have a large biological
impact since they are probably those regions that determine whether we have to
deal with an aurochs or domestic cattle. Presenting the full genome sequencing
of a British aurochs, Park et al. 2015 noted that “important questions remain unanswered, including […] which genomic
regions were subject to selection processes during and after domestication. […]
Finally, the functions of genes showing evidence for positive selection in B.
taurus are enriched for neurobiology, growth, metabolism and immunobiology,
suggesting that these biological processes have been important in the
domestication of cattle”1, what fully supports my view.
It is
therefore my suspicion that we really have to identify the regions coding the
neurobiological, developmental, endocrinologic, morphologic, metabolic and
immunologic differences between aurochs and domestic cattle if we want to make
genetic comparisons that truly matter on a wider biological basis concerning
the nature of the animals and not coincidental variations that have been
accumulated on regions that are barely effected by selection.
It is
therefore not surprising that standard genetic methods that are usually used to
determine simple “relatedness” that look at marker sequences, be it haplotypes,
mitochondrial genes, SNPs or molecular chronometers that are not deeply
effected by phenotypical selection do not show a clear correlation between a
less derived and a strongly derived phenotype, although the latter clearly
implicates a lot of strong directive selection and mutations.
There are
multiple angles to look at a genome, and if we would look at those regions
named above that are probably where we should look for matches with the
aurochs, we would probably receive a different picture because those regions
are directly and highly involved in the shape, form and function of the
organism and directly and highly affected by phenotypic selection.
Furthermore,
and to come back to the chart presented by Rewilding Europe, I am not sure if
the Nei distance is the right tool to compare aurochs and cattle. The Nei
distance was developed to look at the divergence of populations via mutation
and genetic drift. In the case of cattle we do not have nice clean
cladogenesis, but at first we have a dramatic bottleneck, then strong selective
pressure during domestication, then very likely also local introgression on
multiple regions by different regional variants of aurochs, and, not to forget,
very unequal selective pressure on the different populations/lines/breeds of
domestic cattle we see today.
Implications
for “breeding-back”
So we would
actually have to clearly determine those particular regions determining the
defining differences between aurochs and cattle and get an overview over the allelic
differences there. I do not think that it is a problem that we have only one
full aurochs genome yet, because those traits defining the aurochs will,
unsurprisingly, be universal among aurochs. However, I do not think that the
results will be that enchanting or provide an additional directive for
“breeding-back” projects, because of two reasons: 1) the fundamental
differences between aurochs and domestic cattle concerning the seven factors
above will probably be more or less universal among domestic cattle because all
of them show the typical traits of domestication to a more or less clear
extent. It would surprise me if we could still find the genetic make-up for all
defining wild aurochs traits split up and distributed among the cattle of this
world. This could be expected if domestication was an uncoordinated process
where each of the factors was modified separately, which was certainly not the
case as an organism functions as a whole and domestication was a coordinated,
conscious process with a clear objective 2) certainly some breeds will be
closer to the aurochs than others, but the question is how much and if the
extent is relevant at all. For example, if the phenotypically most primitive cattle
on this world show a 1,01% match to the aurochs on those seven crucial factors
(just a symbolic number) while the most domesticated cattle show a 1,009%
match, then the difference has to be considered negligible despite the
primitive cattle having a number of alleles for a primitive morphology. I don’t
think the difference would be that small, but I also do not expect any
miraculous surprises. I think that all domestic cattle on this world are pretty
similar in being domestic, with the derived examples of course carrying it to
the extreme concerning a few morphological and other traits.
The claim
that “no aurochs genes were lost, but just split up and distributed among
domestic cattle” that has been floating around in the web for a while not only
has no empirical support but is also to be considered unlikely for the reasons
outlined above. The dramatic genetic effect of domestication – a narrow genetic
bottleneck at first, strong selection on a large number of genes that have a
dramatic influence on fundamental aspects of the organism – probably
irreversibly and universally purged off a lot of defining wildtype alleles and
therefore aurochs alleles from the domestic cattle gene pool, creating modern
domestic cattle. The occasional local introgression of aurochs may have left
traces in the modern domestic cattle pool (especially in the form of
immunologic adaptions etc.) but certainly it did not alter their domestic
nature. And even if all the defining aurochs genes were indeed still present in
the modern domestic gene pool, and even if we had already identified and
tracked them down in the populations, one should not make illusions over uniting
them by conventional breeding in an anywhere near future because we are probably
talking about at least hundreds of gene loci here. Body size alone is
determined by over 50 loci (in humans)2, and you already see how longsome
it is to achieve the right colour setting although we are dealing only with a
couple of genes there. Therefore, truly genetically reconstructing the aurochs by
selective breeding would be a centuries-long project, and many of the key genes
are probably lost anyway. It would probably be way faster, cheaper and endlessly
more effective to genetically reconstruct an aurochs via either cloning or CRISPR-Cas9.
Therefore, studies
on genetic markers and SNPs are nice, but we are certainly not looking at the
key genes that are relevant for true genetic identity of the animal that the
aurochs originally was. Furthermore, there are unfortunately good reasons to
assume that many of those defining key genes are lost due to the dramatic
process of domestication that all of our modern day cattle went through. That
is why you read that few on “genetic proximity” on this blog. We don’t know
what truly matters yet, and it is likely that we also don’t have it anymore. Thus,
I fear that I have to say that claiming “we are genetically breeding-back the
aurochs” is the same kind of simplicity once practised by the Heck brothers, just
carried onto the next level – even if you back it up with marker or SNP analyses. Please
do not get me wrong, this is just the personal opinion of a biology student sitting
in front of its laptop, therefore I am open for any critique.
Literature
1 Park et al. 2015: Genome sequencing of the extinct Eurasian
wild aurochs, Bos primigenius, illuminates the phylogeography and evolution of
cattle.
2 Visscher 2008: Sizing up human height variation.
One could argue that even the marsupials had a sabertooth-model, and so genetic proximity is obsolete.
ReplyDeleteOn the other hand i think it would be odd if some rare breeds that seem to have some Auroch-related genes others don't have could become extinct while there are breeding-back programms. This doesn't mean that i think that anybody should get focused exclusivly on rare spanish breeds, but if no one does...someone should.
If taken seriously then there are only two breeds of interest on this list : Pajuna and Sayaguesa. I think it would make sense if Axarquia gets analysed also, and maybe Corriente. And there are a few Longhorns that could be interesting.
So why mix these breeds at all ? To get a self-sustainable herd with a low inbreeding-coeffivient.
There could be other breeding-projects like keeping up genes from nearly extinct basal breeds, and maybe adding some african cattle to widen the genetic pool...maybe to get something that resembles about the first domesticated cattle.
I think if just anything gets mixed up, then from a genetic point of view maybe everything could get lost or watered down.
do you understand how fleckvieh scored so high?
ReplyDeleteYes, like I wrote in the article, their study is not that meaningful.
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