Talk:Microcephalin

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[edit] 70% of who?

Some sources say MCHP1 is in 70% of Europeans and East Asians. Other sources say 70% worldwide. Anyone know which one it is for sure? Jonathan Tweet 01:32, 23 January 2007 (UTC)

I don't think enough sampling has been done. With the margins of error, you could probably claim either, although in Sub-Saharan Africa it's well bellow 50%. Bendž|Ť 13:10, 1 July 2007 (UTC)
There's probably not a lot of difference between 70% of (ethnic) Europeans and East Asians and 70% of the world.--Michael C. Price talk 21:02, 1 July 2007 (UTC)

[edit] Tonal language study

Someone took a study on tonal languages and misinterpreted it as a counterpoint to Lahn's study, but the data in the tonal-language study comes from Lahn. Jonathan Tweet 01:19, 30 May 2007 (UTC)

Not at all. The point was that with the new data and Hey's (Actually not just Hey, but Gender et al. 2007) that undersampling in specific areas of Africa may result in erroneous conclusions, but at this point in time it is difficult to say how they are erroneous. If Tishkoff mtGenomic study is correct the center of diversity is not spread over much of SSA but over a suprisingly small area around the Rift Valley lakes and the Eastern congo. This opens up the opportunity of admixtures within Africa at the time of the expansion out of Africa. Hey demonstrates that with hX, which appearred to be of Eurasia admixture origin with a branch time of 1.44 my TMRCA, but found slightly higher diversity in Tanzania/Chad with modest targeted resampling. The observation of these Eurasian 'admixture' examples is not unique, but in every instance when resampling has been done within East/Central Africa that resampling has shown evidence for the putative 'Neandertal' genes in central africa, often with the basal genotype (Harris and Hey PMID 10077682), or increased diversity.
Note the new site on Tonal languages does not mention Archaics or Neandertals at all, in fact it goes out of its way not to mention the conclusions of the previous study. I would say that the authors have backed off that previous claim. If you have not already read Hey et al. I suggest you do, then read Gender et al. 2007 [PMID: 17194802]. Such a claim based on such inadequate sampling goes back some time, the critique of the general method was made following Harding et al 1997 (PMID: 9106523).
This is taken from the preprint version of that paper dealing with Microcephalic haplotype D
"Because genetic information is missing for most sub-Saharan populations, for the 5 populations speaking languages belonging to the Narrow Bantu branch of the Niger-Congo linguistic family (4) (Southeastern and Southwestern Bantu, Turu, Northeastern Bantu, Bakola Pygmy and Bamoun), the frequency information for the amalgamated “Bantu speakers” sample was used to replace the missing data. These 5 populations do not seem to be very different from the point of view of our genetic or linguistic data (paired samples t-tests between all pairs of these populations, separately for the linguistic and genetic data, are ns), and, moreover, they do not differ genetically from the “Bantu speakers” sample (paired t-tests are also ns). These results allow the amalgamation procedure, even if the demographic and linguistic histories of these 5 populations are very different (1,2). This procedure could introduce a bias towards those linguistic features uniform across the sampled Bantu languages and against those showing variation. To control for this, two artificial variants, ASPM-D* and MCPH-D*, were created from ASPM-D and MCPH-D, by replacing their actual frequency values in the 5" - "Linguistic tone is related to the population frequency of the adaptive haplogroups of two brain size genes, ASPM and Microcephalin" Dan Dediu and D. Robert Ladd. PNAS USA [early online]. —The preceding unsigned comment was added by 68.93.82.44 (talk • contribs).

[edit] Premature and misleading claims

According to certain studies these genes may not be directly related to brain size development. Only their mutations cause microcephaly. The study states that the microcephalins have no known contribution to brain size variability, or to intelligence. therefore it may be incorrect to say that these genes are associated with brain development when infact it is only their mutated variants that cause abnormality.

“ Although the role of recessive mutations of both of these genes in producing microcephaly is undisputed, our findings suggest that it is potentially misleading to refer to either of these genes as controlling, regulating or determining human brain size outside the context of the microcephalic state. ”

Furthermore these studies have been criticized for assuming that these genes had anything to do with the upper paleolithic or tonal languages because the scientists did undertake any direct experimentation to test their hypothesis. Therefore it is just pure speculation by Lahn and co that these genes coincide with the upper paleolithic. And with an error of 23000 years means they could have occurred as early as 60000 years ago by which all humans may have still been in Africa or as late as 14000 years ago, long after the the upper paleolithic transitions.


“ Our overall findings do not support a detectable association between the recent adaptive evolution of either ASPM or Microcephalin and changes in IQ. As we enter the post-genomic era, with the number of candidate loci underlying human evolution growing rapidly, our findings highlight the importance of direct experimental validation in elucidating their evolutionary role in shaping the human phenotype ”

.


I am therefore proposing to rewrite its definition as a brain size gene.Muntuwandi 23:48, 1 July 2007 (UTC)

Good research. I only reverted your initial edit as it was unsourced. And be careful of editing referenced statements (e.g. first sentence of the article) such that they no longer concur with the source. I've now integrated it all more concisely. Bendž|Ť 09:51, 2 July 2007 (UTC)


Muntuwandi,
Please read this before attempting to undo my first paragraph again. I think that you misunderstand the word "development." To scientists, "development" is the specialized process of undergoing changes from the embryo to a state of maturity. When you say, "According to certain studies these genes may not be directly related to brain size development. Only their mutations cause microcephaly," it is confusing and contradicting of itself. I assume that you mean brain size "evolution."

Now, my correction of the first paragraph fixed several things. First, it removed the term "microcephalins," which is not a term that you will find in peer-reviewed scientific literature. Unfortunately, I believe that this term is traced back to a NY Times article from late June 2007, and the author apparently did not grasp the concept that "microcephalin" is the name of only MCPH1, not the collective group of MCPH genes. Please read this quote from the abstract of a review by C.Geoffrey Woods, whose lab (I believe) was the first to start identifying genetic loci that are responsible for Primary Microcephaly:

"Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental disorder. It is characterized by two principal features, microcephaly present at birth and nonprogressive mental retardation. The microcephaly is the consequence of a small but architecturally normal brain, and it is the cerebral cortex that shows the greatest size reduction. There are at least seven MCPH loci, and four of the genes have been identified: MCPH1, encoding Microcephalin; MCPH3, encoding CDK5RAP2; MCPH5, encoding ASPM; and MCPH6, encoding CENPJ."

I believe that you undid my paragraph because "some people with microcephaly are completely normal." The above quote from the review also describes the clinical criteria for diagnosis of Autosomal recessive primary microcephaly or MCPH. This includes, a head size that is four or more standard deviations smaller than that of age- and sex-matched means AND mental retardation. Instead of "some people with microcephaly," do you mean, "people with the various haplotypes are completely normal?" If so, you are right! Please do not confuse severe mutations of MCPH genes (that likely produce no protein at all) with the various MCPH haplotypes (which result from single nucleotide changes in the gene that could lead to adaptive changes within the protein). MCPH mutations are studied to determine how these proteins are necessary during DEVELOPMENT. MCPH haplotypes are studied to determine how or if these proteins led to brain enhancements during human EVOLUTION. I apologize for the lengthy explanation; however, I spent a lot of time writing that paragraph and would have appreciated a discussion on this page rather than an "undo." Jrickmyre 23:55, 2 September 2007 (UTC)

Jrickmyre, a lot of time was spent too on the original information by myself and other editors such as Bendzh. I appreciate your effort in cleaning up the terminology, however I believe you have inserted some information that may not be entirely accurate. You mention that microcephaly is characterised by mental retardation when the article on Microcephaly indicates "Hyperactivity and mental retardation are common occurrences, although the degree of each varies". Finally your statements are very supportive of the view that microcephalin genes have been strongly selected whereas there is an equal body of evidence indicating otherwise. Muntuwandi 00:37, 3 September 2007 (UTC)

You have given the definition for Microcephaly; however, the topic of this article, if I am not mistaken, is the genes that cause the disease known as Autosomal Recessive Primary Microcephaly (MCPH), a specific category of Microcephaly. You need to realize that this particular form of microcephaly is included in the group of microcephaly diseases that present mental retardation. This is mentioned in every review of the topic of MCPH. AGAIN, do not confuse this with the broader term of microcephaly. I looked up a couple of reviews, here are the paragraphs that specifically mention the clinical phenotype:

“

Autosomal recessive primary microcephaly

Individuals with autosomal recessive primary microcephaly (MCPH) are born with a significantly small head circumference (-4 to -12 SD) and are mentally retarded, but have no other abnormal findings or neurological features (Figure 2; [11.•]). Brain scans show that the whole brain is reduced in size, but it is the cerebral cortex that is most severely affected [11.• and 12.••]. Two of the genes that cause MCPH have recently been discovered, Microcephalin and abnormal spindle in microcephaly (ASPM) [12.•• and 13.•]. All of the mutations are predicted to lead to a truncated protein and for ASPM, at least, there is no correlation between the position of the mutation and the degree of microcephaly. This suggests that nonsense medicated RNA decay occurs and that a functional absence of the ASPM protein is what causes MCPH [12.•• and 14.]. Both genes are expressed in embryonic and foetal mammalian neuroepithelium [12.•• and 13.•], which lines the ventricles of the developing brain ( Figure 1).
from Woods, C.G. (2004) Human Microcephaly. Current Opinion in Neurobiology 14:112-117.

 ”

"Box 1. Current working clinical definition of autosomal recessive primary microcephaly
• Microcephaly is evident at birth and is at least three standard deviations below the age- and sex-adjusted mean.
• The degree of microcephaly does not vary throughout life. Within the same family, HC usually does not vary by > 2SD between affected individuals.
• Microcephaly presents mental retardation (from mild to severe) but no other neurological finding such as spasticity or progressive cognitive decline. Fits are unusual, but do not exclude the diagnosis [33]. Recently, a MCPH individual with borderline mental retardation (intelligence quotience = 74, with normal verbal skills) has been reported [8].
• Height, weight, appearance, chromosome analysis and brain scan are normal in the majority of individuals with MCPH.
• Specifically for patients linked to the 1st MCPH locus, MCPH1, cytogenetic analysis reveals an increased proportion of prophase-like cells. A reduction in height can occur, but the HC is always significantly more reduced than height. On MRI scan, some patients show evidence of periventricular neuronal heterotopias, which is suggestive of neuronal migration defects 16, 18 and 19."
From Cox et al. (2006). What primary microcephaly can tell us about brain growth. Trends Mol Med. 12:358-366.

You will be interested to know that there has been a patient with a mutation in MCPH1 that only led to very mild mental retardation. The earliest reports of MCPH1 mutations were the results of a severe truncation near the amino-terminus (i.e. the beginning) of the protein making it unlikely for the production of the full-length protein. This new case is the result of a conserved amino acid substitution within the first BRCT domain of MCPH1. You can at least read the abstract of that article here[1]. Now, I've already given up on trying to fix that paragraph again. I leave it in your hands to do so because I have my own MCPH (specifically MCPH1) articles to write. If you are truly interested in this topic, I encourage you to read everything you can about it in peer-reviewed scientific literature. A good place to start searching is on PubMed[2]. If you type "MCPH1" in the search box, you will find at least 40 articles on the topic of MCPH1/Microcephalin alone. Good luck.Jrickmyre 02:59, 5 September 2007 (UTC)

[edit] a lot better

This article was pretty thin when I first started editing it. It's gotten a lot better. Good work. Jonathan Tweet 14:15, 2 July 2007 (UTC)

[edit] "microcephalins"

I just changed the first paragraph to remove the incorrect term "microcephalins" and to describe the disease in more detail while very briefly hitting on the science of the MCPH genes. I googled "microcephalins" and found a NY Times article that used this term, so I'm guessing that's where it came from? At the time MCPH1 was cloned, Jackson et al. 2002 gave it the name Microcephalin. So, Microcephalin is only used as a name for MCPH1 not as the full name for MCPH (MCPH is the abbreviated form for Autosomal Recessive Primary Microcephaly). The other MCPH genes have (or will have) their own gene names. Is there any way to change the title of the article? Based on the other information in this article, I assume that the topic is supposed to be MCPH genes.
I also switched some of the gene symbols and alt symbols around to specify the correct gene names (e.g. ASPM is the actual name of MCPH5, so MCPH5 should be listed as the alt). Jrickmyre 08:24, 2 September 2007 (UTC)

I came up with the "microcephalins" independently of the newspapers, and I can see now it's not entirely conventional. What you did with the gene boxes is fine, but the opening paragraph shouldn't be changed so drastically. This is an article specifically on the genes that have been linked to microcephaly (which has an article of its own), and speculation regarding the functions they may have other than causing that disease when non-functional. There is a paragraph that explains the alternate naming of some of the genes. I'll try a moderate rewording of the lead. Bendž|Ť 16:51, 3 September 2007 (UTC)

The genes that were listed in the boxes to the right were all of the genes linked specifically to Autosomal Recessive Primary Microcephaly (MCPH), and no other types of microcephaly genes were listed (there are several others). Therefore, I made the assumption that this article was indeed meant to encompass the genes that cause MCPH. The drastic changes were necessary to match the introduction to those specific genes. Please see my reply to Muntuwandi above.Jrickmyre 03:04, 5 September 2007 (UTC)


[edit] Update

Biol. Lett. (2007) 3, 157–160 doi:10.1098/rsbl.2006.0586

Turns out the entire brouhaha was bogus. The function of these genes seems in effect purely morphological, not mental. Of course brain anatomy affetcs the mind somehow as can be seen in disruptive alleles e.g. causing microcephaly. But whatever the connection between MCPH1 and ASPM and mental functions may be, it is drowned in random noise and stochasticity.

If your argument was driven by science and not intellectual short-sightedness, you should have expected this already. If it were that linear, we would have long "decoded" the mind instead of having shite. Dysmorodrepanis 20:30, 12 September 2007 (UTC)

Who are you addressing and what are you trying to say? The refuted brouhaha is entirely at the expense of racists, and has nought to do with linguistics. It simply concurs with previous research while confirming the limitations of previous findings. Bendž|Ť 22:23, 12 September 2007 (UTC)

[edit] Is this gene "a haplogroup"?

A derived form of MCPH1 called haplogroup D

Is that correct? I highly suspect that it was intended to mean a gene associated with the haplogroup D, not that it is called haplogroup D. --Extremophile (talk) 19:20, 23 November 2007 (UTC)