Has a new mutation lead to the identification of the G locus ?

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In 1975, the Grey Agouti gerbil was first discovered in a London petshop, it later died out but a couple of years later it appeared again and is now very common in the UK and Europe, although in the USA it is still regarded as a relatively uncommon coat colour. The fur colour closely resembles the chinchilla mutation of the albino series of alleles (C locus) in mice and other domestic livestock. Breeding tests conducted with the mutant showed that this wasn’t the case and in 1985 it led to the publication of the early research in the Journal of Heredity;

Leiper, B.D. & Robinson, R. 1985. Gray mutant in the Mongolian gerbil. The Journal of Heredity, 76, 473.

The paper discusses the phenotype of the gerbil, and the mutant was also tested to see whether it was an allele of albinism. This was essentially undertaken because among the various classes of mammalian coat colour mutations, those that effectively remove phaeomelanin (yellow pigments) but not eumelanin (black pigments) would normally be regarded as an allele of the albino locus (C locus in gerbils) and especially  if they are inherited as a recessive to the wild type (agouti). Mutations that differentially remove phaeomelanin from the coat colour, but are not alleles of the albino locus are particularly uncommon and at the time of writing the paper only a few examples existed. These were grey-lethal and grizzled in the house mouse and dark grey and lethal grey in the Syrian hamster. However, both grey-lethal and lethal grey are known to cause the demise of the homozygotes, while grizzled and dark grey animals tend to be undersized and have reduced viability. This wasn’t the case for the Grey mutant in the Mongolian gerbil, which was of normal size with good viability. The authors tentatively designated the symbol ‘g’ (grey) to the mutation. The authors also systematically combined the grey gene to other known colour genes available at the time, producing several new coat colour varieties. These were:

Sepia - Fanciers now know this colour as slate (it was previously called Blue in the UK)

Pale cream or Ivory – (U.S.-  this colour is now known as Ivory Cream. UK-  it is now known as White-Bellied Cream.)

Off-White-Fanciers now refer to this colour as Ruby-Eyed White.

The new Grey locus nomenclature was quickly adopted by gerbil fanciers but apart from the early work that was undertaken by the geneticists, very little was known about this particular locus or its mutant allele other than its ability to drastically  reduce phaeomelanin in the coat, while only marginally reducing eumelanin. However, with the recent discovery of a new recessive allelomorph on this locus, which when homozygous, removes most pigments from the coat and eye on both Agouti and non-agouti, it has now enabled us to possibly ascertain the true identity of the G locus.

Discovery of the New Mutation

Around the year 2000, Michele Inman, a gerbil breeder from Illinois, U.S.A. bought several gerbils from a pet shop and it is from these foundation gerbils that Michelle first noticed, then eventually isolated the mutation. In late 2008 she contacted myself through the eGerbil website.  Michelle had already done a great deal by test breeding the mutation on many known colours, and arrived at the conclusion that the mutation resided at our currently known Grey locus.

Description of the Mutation

On both Agouti and non-agouti coat backgrounds, the new mutant gene when homozygous produces a cream gerbil with dark ruby eyes, The coat colour is very similar to the White–Bellied Cream and the Self Cream ( syn. C-separator/Red-Eyed Silver Nutmeg). A single recessive gene when combined with the existing Slate coat colour produces the colour Azure slate, which is a further dilution of Slate that lends to the coat a subtle bluish tone. Although it is superficially similar to the blue coat colour caused by the dilute gene, on closer examination it is quite different.

When the gene is combined with extension of yellow ‘ee’ it produces an off-white gerbil with ruby eyes. The colour is similar to the known coat variety, Ruby-Eyed White.

This new mutant, and the entire locus, mimic other known well known coat colour phenotypes. However the nature of its importance lies not in any new colours produced, but in how it enabled us to identify the true identity of the G locus.

Identifying the Alleles of the Grey Locus

As mentioned in the research paper on the Grey mutant, there are only a few coat phenotypes in other species that resemble the chinchillated appearance of the Grey Agouti gerbil, and although these coat colours looked similar to the Grey Agouti, they differed in many other respects. Since that initial research, other grey mutants have arisen in mice that may have help shed some light on its true identity.

To confirm that the mutant was indeed an allele of the Grey locus, I instructed Michelle to conduct some simple complementation tests for allelism. Once this was proven we could move to the next step which was researching existing mouse gene databases looking for coat colour comparisons of the mutant alleles.  This in itself was quite a task as not only had we to find a coat colour that matched the new mutant, but also find another allele of the same locus that produced similar phenotypes to our well known Grey Agouti and Slate coat colours.

My initial thoughts of the new mutant gene were that we were looking at some form of oculocutaneous albinism. Even though this form of albinism was disregarded in early research on the g gene (the g gene wasn’t an allele of the albino locus, so albinism was dismissed) there are several other types of coat and eye albinism, each having their own distinct phenotypes. Also, if one takes a much closer look at the grey gene we can actually observe slight OCA taking place. We can not only see a dilution of the coat, but a slight dilution of the eye.  Although eye dilution is subtle, it becomes obvious on a non-agouti background, and especially so if you observe the eye under a bright light where it glows a very dark ruby. Obviously the two alleles, 'g(x)' and 'g' were similar, with 'g(x)' being severe in its actions , but we needed a match of phenotypes to a comparable locus in other species, if that was possible, so naturally we turned to the house mouse to hopefully find our answers.

Comparing coat colours and gene action

Our hunt for coat colour comparisons with mouse alleles gained momentum when our colleague Sandy Van Eysinga from the M.I.G. (Mutation Investigation Group) offered to help Michelle and me. Between the three of us we all clearly decided that one of the main candidates I initially drew up in a short list bore striking similarities to Michelle’s 'g(x)g(x)' gerbils which, over the years, Michelle had come to name “Satins”. In mice, this particular coat phenotype is known as underwhite, and it essentially bleaches the coat of the animal to a cream/beige colour and the eyes to a dark ruby. However there was virtually no information available as to whether this locus had other mutated allelomorphs or what the phenotypes of these alleles looked like.

After several fruitless months searching various research papers, luck was finally on our side when I was reading through a paper about two further alleles on the underwhite locus. These mutant alleles were known as underwhite dense and Underwhite dominant brown. Although I initially ruled out dominant brown because it was a semi-dominant over the wild type allele, the underwhite dense in the study sounded very similar to our slate coat colour variety. I should explain here that most studies on underwhite and its various mutated alleles are normally carried out on a non-agouti background, and  finding breeding data on Agouti was non-existant!  However we desperately needed to know what the coat colour looked like on an agouti background! because without this confirmation everything was still guesswork.

Further in to the research paper, the authors gave out some important data on uw(d) on Agouti, and this helped us ascertain what its coat colour phenotype looked like.  Also within the paper it contained breeding studies conducted on the effects of uw(d) (non-agouti) when combined with recessive yellow and pink-eyed dilution, this too gave us further insights on the gene and helped draw parallels to the grey allele in the Mongolian gerbil.

You can download a copy of this research paper in pdf format from here.

Adobe reader is required.

“The Underwhite (uw) Locus Acts Autonomously and Reduces the Production of Melanin”- Anne L. Lehman, Willys K. Silvers, Neelu Puri, Kasumasa Wakamatsu, Shosuke Ito, Murray H. Brilliant.

Below is the abstract from the research paper;

“The mouse has provided several significant models for hypopigmentation disorders, including the major forms of albinism. Mutations at the mouse underwhite locus confer one of the most severe hypopigmentation phenotypes, similar to mutations at the pink-eyed dilution locus that is a model for type 2 oculocutaneous albinism. A melanocyte cell line established from underwhite mutant mice failed to pigment under conditions that support pigment production in wild-type melanocytes and melanoblasts from underwhite skin graft transplants failed to produce melanin in normal skin, demonstrating that the action of the gene encoded by the underwhite locus is intrinsic to melanocytes. Mice with mutations at the underwhite locus and either the pink-eyed dilution locus or the melanocortin receptor 1 locus exhibited more severe hypopigmentation than either mutation alone, suggesting that the actions of these genes are independent. These results demonstrate that the underwhite locus is a major determinant of mammalian pigmentation.”

 As you can read from the  extract here, it seems that the underwhite dense mutation on an agouti mouse closely resembles the chinchilla mouse coat colour. The studies conducted in this research paper may have helped the gerbil community to identify the existing grey mutation as underwhite dense and identified Michelle Inman’s mutation that she has worked on since 2000 as underwhite.  It has also helped resolve the issues regarding the identity and also the possible function of the G locus in the Mongolian gerbil.

Ed Cope

You can read a much more detailed account of the discovery of this new mutation in the Mongolian gerbil at Michelle Inman's website here