{"id":2353,"date":"2010-06-04T13:58:59","date_gmt":"2010-06-04T11:58:59","guid":{"rendered":"http:\/\/localhost\/azgad\/wordpress\/?p=2353"},"modified":"2010-06-04T13:58:59","modified_gmt":"2010-06-04T11:58:59","slug":"evolutionary-profits-and-losses","status":"publish","type":"post","link":"https:\/\/azgad.com\/?p=2353","title":{"rendered":"Evolutionary profits and losses"},"content":{"rendered":"

.
\nThe disruption of melatonin production in laboratory mouse strains represents
\nan apparent evolutionary advantage in terms of reproductive development<\/strong>
\n.
\nAnimal models can yield valuable insights into the biology of human disorders,
\nalthough they can also introduce additional levels of complexity that may make
\nit a challenge to experimentally untangle the bases for specific phenotypes.
\n.<\/p>\n

Tadafumi Kato and Takaoki Kasahara of the RIKEN Brain Science Institute in Wako
\nran into such a challenge in their attempts to characterize abnormalities in the activity
\n of melatonin, a hormone that fine-tunes the circadian rhythms that establish an organism\u2019s
\nday\u2013night cycle, in their mouse model of bipolar disorder. \u201cSince early times, researchers
\n and psychiatrists have believed that melatonin has something to do with mood disorders,
\n because many patients experience sleep disturbance and light therapy is used effectively
\n in the treatment of seasonal affective disorder,\u201d says Kasahara. However, they quickly found
\ntheir efforts thwarted by the utter absence of melatonin from their laboratory mice.
\n.
\nIndeed, a growing body of evidence suggests that several strains of laboratory mice\u2014including
\nthe C57BL\/6J (B6J) line used by Kato and Kasahara\u2014are deficient in the production of
\n melatonin, a process that depends on the sequential action of two enzymes: arylalkylamine
\n N-acetyltransferase (AANAT) and hydroxyindole O-methyltransferase (HIOMT).
\nScientists have successfully identified the mouse Aanat gene, and have even uncovered an
\n inactivating mutation within this gene in B6J mice. However, even with high-quality mouse
\ngenome sequence data available, nobody has yet succeeded in tracking down its partner,
\n Hiomt. \u201cI studied the mechanism of circadian clocks when I was a PhD student, and I heard
\nthat mouse Hiomt was really enigmatic,\u201d recalls Kasahara, \u201cand even after being away from
\nthe field for about six years, I became aware that mouse Hiomt still had not been identified.\u201d
\n.
\nThis is no longer the case, thanks to an extensive analysis of the mouse genome by Kato,
\nKasahara and colleagues1. Using the rat HIOMT protein sequence as a basis for comparis
\non they have finally managed to uncover this mysterious gene and have thereby revealed
\n why it has remained hidden from scientists for so long.
\nNotably, mouse HIOMT bears only limited resemblance to its counterparts in other species,
\n with an amino acid sequence that is less than 70% identical to that of the rat protein.
\nFurthermore, this gene was likely masked by its residence within the pseudoautosomal
\nregion (PAR), a poorly characterized stretch of DNA within the sex chromosomes that
\n enables them to efficiently \u2018pair up\u2019 and undergo recombination during meiosis. \u201cThe
\n PAR contains extremely repetitive sequences and high guanine-cytosine content, both
\n of which make it difficult to sequence using either traditional or next-generation sequencing
\nmethods,\u201d says Kasahara.
\n.
\nDevelopmental consequences<\/strong>
\n.
\nCloser analysis of the sequence of this gene revealed two notable sequence variations in
\nB6J mice relative to MSM animals\u2014a strain derived more recently from wild mice that exhibits
\nnormal melatonin production. Both of these changes affect the amino acid sequence of the
\n encoded protein, and the investigators showed that each mutation leads to a strong reduction
\n in HIOMT levels. These mutations also proved to be widespread among a variety of other
\n inbred mouse strains, including several lines commonly employed in laboratory research.
\n.
\nKato, Kasahara and colleagues also noted that although this HIOMT deficiency appears to
\n have a limited impact on circadian behaviors, it has a clear effect on gonadal development;
\nmelatonin-deficient animals with the B6J versions of the Hiomt and\/or Aanat genes exhibited
\nsignificantly greater testicular growth than their melatonin-producing counterparts. Conversely,
\n in experiments with ICR mice, another melatonin-deficient strain, the researchers showed that
\n treatment with melatonin was associated with a reduction in testicular weight.
\n.
\nThese findings are in keeping with other data showing a vital link between melatonin and
\n reproductive development\u2014including observations in human patients. \u201cChildren with little
\n or no melatonin due to pineal tumors often show premature sexual maturation,\u201d says
\nKasahara.
\n.
\nEvolution in a cage<\/strong>
\n.
\nBecause these defects appear to be specifically prevalent among cultivated strains of
\n laboratory mice, it appears likely that there is some manner of selection taking place that
\nfavors the emergence of strains with reduced melatonin levels and accelerated
\nreproductive development\u2014even if this evolution was unintentional and, until now,
\ninvisible. This finding is supported by similar research in domesticated chickens,
\n which has spotlighted the emergence of other gene variations that may potentially
\n influence the same developmental pathway2. \u201cOne of the most intriguing [variants] is
\nfound in the gene encoding the receptor for thyroid-stimulating hormone, because
\nTSH and melatonin are closely related in seasonal breeding,\u201d says Kasahara.
\n.<\/p>\n

These findings could also have potential implications for previous animal studies
\nthat have investigated circadian rhythms, given that much of this research has been
\nconducted in B6J and other inbred strains. For example, one recent study has shown
\nthat the circadian rhythm defects observed in the widely used B6J-derived Clock mutant
\n mice are markedly diminished in the presence of normal levels of melatonin.
\n.
\nThese findings will closely inform future work from Kasahara and Kato, who are in the process
\nof engineering a melatonin-producing B6J strain for use in their future investigations of
\nmood disorders. However, Kasahara also suggests that conventional laboratory strains
\n in general may be too interbred for their own good. \u201cOur B6J mouse model for mood
\ndisorder has many phenotypes similar to bipolar disorder, but they don\u2019t get manic
\n spontaneously,\u201d he says. \u201cI hypothesize that laboratory mice have lost their potential
\n to develop manic or aggressive episodes, and we are consequently using wild-derived
\n mice, which are very aggressive, alert and agile in order to study these disorders.\u201d<\/p>\n","protected":false},"excerpt":{"rendered":"

. The disruption of melatonin production in laboratory mouse strains represents an apparent evolutionary advantage in terms of reproductive development . Animal models can yield valuable insights into the biology of human disorders, although they can also introduce additional levels of complexity that may make it a challenge to experimentally untangle the bases for specific … <\/p>\n

\u05d4\u05de\u05e9\u05d9\u05db\u05d5 \u05d1\u05e7\u05e8\u05d9\u05d0\u05d4<\/a><\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_monsterinsights_skip_tracking":false,"_monsterinsights_sitenote_active":false,"_monsterinsights_sitenote_note":"","_monsterinsights_sitenote_category":0,"footnotes":""},"categories":[10],"tags":[131,282,513,186],"class_list":["post-2353","post","type-post","status-publish","format-standard","hentry","category-10","tag-131","tag-282","tag-513","tag-186","nodate","item-wrap"],"_links":{"self":[{"href":"https:\/\/azgad.com\/index.php?rest_route=\/wp\/v2\/posts\/2353","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/azgad.com\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/azgad.com\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/azgad.com\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/azgad.com\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=2353"}],"version-history":[{"count":1,"href":"https:\/\/azgad.com\/index.php?rest_route=\/wp\/v2\/posts\/2353\/revisions"}],"predecessor-version":[{"id":2354,"href":"https:\/\/azgad.com\/index.php?rest_route=\/wp\/v2\/posts\/2353\/revisions\/2354"}],"wp:attachment":[{"href":"https:\/\/azgad.com\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=2353"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/azgad.com\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=2353"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/azgad.com\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=2353"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}