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Old 11-05-2002, 10:10 AM   #1
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Post Abundant Raw Material for Cis-Regulatory Evolution in Humans.

<a href="http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=124116 08&dopt=Abstract" target="_blank">Mol Biol Evol 2002 Nov;19 11:1991-2004</a>

Abundant Raw Material for Cis-Regulatory Evolution in Humans.

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Changes in gene expression and regulation-due in particular to the evolution of cis-regulatory DNA sequences-may underlie many evolutionary changes in phenotypes, yet little is known about the distribution of such variation in populations. We present in this study the first survey of experimentally validated functional cis-regulatory polymorphism. These data are derived from more than 140 polymorphisms involved in the regulation of 107 genes in Homo sapiens, the eukaryote species with the most available data. We find that functional cis-regulatory variation is widespread in the human genome and that the consequent variation in gene expression is twofold or greater for 63% of the genes surveyed. Transcription factor-DNA interactions are highly polymorphic, and regulatory interactions have been gained and lost within human populations. On average, humans are heterozygous at more functional cis-regulatory sites &gt;16,000 ,than at amino acid positions &lt;13,000, in part because of an overrepresentation among the former in multiallelic tandem repeat variation, especially ACn dinucleotide microsatellites. The role of microsatellites in gene expression variation may provide a larger store of heritable phenotypic variation, and a more rapid mutational input of such variation, than has been realized. Finally, we outline the distinctive consequences of cis-regulatory variation for the genotype-phenotype relationship, including ubiquitous epistasis and genotype-by-environment interactions, as well as underappreciated modes of pleiotropy and overdominance. Ordinary small-scale mutations contribute to pervasive variation in transcription rates and consequently to patterns of human phenotypic variation.
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Old 11-05-2002, 10:33 AM   #2
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thanks, theyeti,

cool stuff - too bad I don't have time to read all these new discoveries.

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Old 11-05-2002, 11:50 AM   #3
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Good post. This thread may not get much play though because of the complexity of the subject matter. I myself have only a tentative grasp of it, but I think regulator genes are fascinating and that they explain a lot about human evolution.
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Old 11-05-2002, 12:19 PM   #4
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Quote:
Originally posted by GeoTheo:
<strong>Good post. This thread may not get much play though because of the complexity of the subject matter. I myself have only a tentative grasp of it, but I think regulator genes are fascinating and that they explain a lot about human evolution.</strong>
Just to be clear, these are not regulator genes being talked about here. It's a minor point, but when talking about a gene, you're almost always referring to a DNA sequence which codes for an RNA . This is not the case with cis and other regulatory regions. These are nucleotide sequences of varying lengths that are located on the same strand (if they're cis) as the gene that they regulate. But they do not code for a product. They typically work by binding transcription factors that control when the gene is expressed and in what quantity. They can also bind enhancers or repressors and other stuff. One cool thing is that many of these polymorphisms allow more than one transcription factor to bind. This means they represent gain-of-function mutations. Another cool thing is that most of these polymorphisms -- and all of the ones studied here had an effect on function -- were SNPs (single nucleotide polymorphisms). This means that the most boring and common kind of mutation is causing most of our functional variation. There's no need to invoke "macro-mutation" or other kinds of major DNA variants to explain the phenotypic differences, for example, between us and chimps. In a thread a week or two ago I think it was Monkeybot who remarked that she believed that most differences between us and our chimp cousins were due changes in cis-regulatory regions. This has been a common assumption for some time, but now someone's gone out and demonstrated it..

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Old 11-05-2002, 12:30 PM   #5
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Is what you are talking about related to Operons?
Sounds like you are talking about somthing similar. What I get out of the whole thing is that the building blocks were there (genes) We(humans) just do different things with them. This can be caused by cis acting mutations.
(I just dropped molecular genetics because I feel I need some chemistry. I have no idea why biochemistry was not a pre-requisite.)
My point was I doubt any creationist will come by here and debate you, but I think it is interesting even though my grasp of the subject matter is rather weak.
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Old 11-05-2002, 01:06 PM   #6
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Quote:
Originally posted by GeoTheo:
<strong>Is what you are talking about related to Operons?</strong>
Sort of. Operons are found in prokaryotes and consist of a highly streamlined set of genes that are usually all under the control of a few promoter and/or repressor regions, often regulated via feedback. Eukaryotic genomes, on the other hand, are arranged in a much messier fashion, and each gene has its own start site and can be regulated independently.

So it's similar in that operons have non-coding regulatory regions. But humans (and other eukaryotes) don't have operons.

Quote:

Sounds like you are talking about somthing similar. What I get out of the whole thing is that the building blocks were there (genes) We (humans) just do different things with them. This can be caused by cis acting mutations.
Yes, basically. In other words, there's a lot of variation in the way our genes are regulated, and this variation is the "raw material' for much of our evolution. This is why, for example, us and chimps have so much of our DNA in common, yet can be quite distinct phenotypically.

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(I just dropped molecular genetics because I feel I need some chemistry. I have no idea why biochemistry was not a pre-requisite.)
I suggest taking molecular biology first, and perhaps a course in standard genetics (sometimes the two are lumped together). Biochem is good too, but having to memorize things like the Krebs cycle won't help you much with molecular genetics.

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Old 11-05-2002, 02:15 PM   #7
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Yeti, I think you are right. I need to take molecular biology and then regular genetics. Thank you. It's hard to figure out what to take in order to understand things I can't understand, when I haven't taken the couses I need to understand them! I withdrew with a passing grade, but I would like to get more out of the class than a grade. I want to learn stuff. I also don't like professors that teach way over everyones head and then grade on a curve. It's like they are saying "Here's a gift you hopeless retard." I don't like having a 45 average in a class and having a C. The way I look at it, if the highest grade in the class is an 80 there is somthing wrong.
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