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 fairly uncommon variety. The coat colour closely resembles the chinchilla mutation  of the albino series of alleles (C locus) in mice and other domestic livestock.  Research on the mutant showed that this wasn’t the case and in 1985 it led to the publication of this 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 albinism (C locus in gerbils) and especially so 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. 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 Mongolian gerbils, which is of normal size with good viability. The authors tentatively designated the symbol ‘g’ (grey) to the mutation. The authors also systematically combined the ‘g’ gene to other known mutants at the time, producing several new coat colours. These were;

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

Pale cream or Ivory – (U.S. it 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.

Thus the G or Greying locus was quickly adopted by gerbil fanciers and not much else was known about this particular locus or its mutant allele other than it drastically reducing 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, virtually removes all pigment from the coat and eye, it has enabled us to possibly ascertain the true identity of the G locus itself.

Description of the new mutation.

On both Agouti and Non-Agouti backgrounds the new mutant gene when it is in its homozygous state produces a cream gerbil with dark ruby eyes, The coat colour is very similar to the White–Bellied Cream and the Self Cream (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 gene, and now it seems the entire locus, mimics other known well known phenotypes. However the nature of its importance lies not in any new colours produced, but in how it has enabled us to possibly identify the true nature of the G locus.

Identifying the alleles of the G locus.

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

Personal communications with Michelle

When Michelle first contacted me about her discovery of a new mutation that she believed was on the G locus, my initial confusion centred on the fact that the gene produced a cream gerbil with ruby eyes. This fact alone brought into question the Grey Locus for me. We certainly weren’t seeing a grey animal here, but one that has had virtually all the pigment removed. So where ‘gg’ animals produce a gray phenotype on an an agouti background and a slate gray phenotype on a non-agouti background, this allele which Michelle referred to as ‘g(x)’ removed virtually all the pigments on either agouti or non-agouti backgrounds, leaving only traces of phaeomelanin (yellow pigments) in the coat coupled with a dark ruby eye. So the task ahead was two-fold; I wanted Michelle to do further allelic breeding with this animal to prove it was indeed on the G locus, plus we not only needed to find a comparable coat colour to the new mutant gene in another species, but also find an allele of the same locus that produced the similar grey and slate phenotypes of our gray agouti and slates.  This way, maybe we could then have a at least a fair chance of identifying the entire locus.

My initial thoughts of the new mutant gene were that we were looking at some form of oculocutaneous albinism. Even though 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 our ‘g’ gene we can actually observe slight OCA taking place. We can not only see a dilution of the coat, but a slight dilution in the eye as well. Although eye dilution is subtle, this effect is much more 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, g(x) being much more extreme in its actions, but we needed a match of phenotypes to a comparable locus in other species if at all possible, so naturally we turned to the house mouse to hopefully find our answers.

With Oculocutaneous albinism there are 4 main forms of this syndrome, and several forms of Hermansky-Pudlack syndrome plus Chediak-Higashi syndrome that account for the various forms of albinism in patients. These can be viewed at the Albinism Database of the University of Minnesota ;

http://albinismdb.med.umn.edu/

All these syndromes have their equivalent mouse analogues, and these particular mice all have distinct diluted phenotypes because of the actions that the mutant genes takes on their coat and eye colours. For examples of the coat colour mutations of these genes you can visit this page;

http://www.espcr.org/micemut/

This database represents many mutations in just the mouse alone, so it wasn’t an easy task matching these three phenotypes of our Grey locus, then mapping both alleles to a single locus. There were several which behaved like Michelle’s new mutation, but didn’t have a corresponding allele on the same locus that either looked like the Grey Agouti or Slate, and others which looked like either grey agouti or slate, but again didn’t have a corresponding allele that phenotypically resembled the g(x) gene, i.e. a cream gerbil with ruby eyes.

In one of our first communications, Michelle asked what I thought the gene was, however I knew that there could be many possible candidates and suggested to initially explore types of diluting genes. Not genes such as Dilute or Leaden, but ones that led to eye and coat dilution similar to C and P mutations, that we already have in our gerbils. Mutations on both of these loci are forms of oculocutaneous albinism. I set out a shortlist of known avenues to explore and hopefully we could research these together, check the locus they belonged to, and maybe we could find a match for Michelle’s g(x) mutation and also our known g mutation residing on the same locus. (You can read this early communication in detail on Michelle’s “Wonderings & Musings” page here)

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.  Between the three of us we all clearly decided that one of the main candidates I initially drew up 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.

However, after several fruitless months searching, luck was finally on our side when I was reading through a research 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 I desperately needed to know what the coat colour looked like on an agouti background! Without this confirmation everything was still guesswork.

The hunt was now on to find out what effect underwhite dense had on an agouti mouse, and the answers may lie in the research paper, “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.

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

Adobe reader is required.

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.”

Firstly it was the phenotypes that were produced when non-agouti underwhite dense (which closely resembles our slate coat colour) was crossed to both Argente mice (agouti background) and recessive yellow mice (on a non-agouti background) Although the phenotype of ‘aaee’ mice differs from gerbils in that it completely masks black, whereas in the gerbil’s coat it only partially masks as an adult to produce the nutmeg coat colour, the phenotypes of the double mutant phenotypes aauw(d)uw(d)ee and AAuw(d)uw(d)pp superficially resembled our Silver Nutmeg and REW coat varieties. Another similarity also existed between Michelle’s mutation and the underwhite mutation. In the original description of underwhite (Dickie 1964) the fur is said to be beige with a white undercoat and the eyes which are pink at birth subsequently darken with age. This darkening of the eye is what Michelle also observed with her Satin gerbils. Further into the paper it revealed more important details about underwhite dense on an agouti background, which finally confirmed what the coat colour looked like;

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

Ed Cope

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