Genome complexity: what genes do and don't do; continued (Introduction)

by David Turell , Sunday, February 24, 2019, 19:21 (2098 days ago) @ David Turell

Second part of the article just presented:

"more evolved functions—and associated diseases—depend upon the vast regulatory networks mentioned above, and thousands of genes. Far from acting as single-minded executives, genes are typically flanked, on the DNA sequence, by a dozen or more “regulatory” sequences used by wider cell signals and their dynamics to control genetic transcription.

"This explains why humans seem to have only a few more genes than flies or mice (around 20,000), while a carrot has 45,000! There is no correlation between the complexity of living things and the number of genes they have. But there is a correlation with the evolving complexity of regulatory networks. Counting genes to understand the whole is like judging a body of literature by counting letters. It can’t be done.

"All of this provides a fraught background for modern gene association studies. What’s more, the statistical analyses that power these studies are, themselves, full of pitfalls. First, the methods for computing polygenic scores, in which millions of variables are analyzed by statistical manipulation, provides huge opportunities for false positives. Very large databases—even randomly generated ones—can contain large numbers of meaningless correlations; and statistical significance values can be hugely inflated by invalid assumptions.

'In polygenic score estimations, for example, it is assumed that SNP associations [single nucleotide polymorphisms] can be simply added together, as if beans in a bag, with no effects on each other, or from the environment. Then, as the National Institute of Health website reminds us, the majority of SNPs are functionally irrelevant anyway.

***

"Another wrench in the works has been the discovery that a gene product typically undergoes rearrangements before being put to use. It means that different proteins, with potentially widely different functions, can be produced from the same gene: not one for one, as the central dogma has told us. Again, the instructions for such rearrangements are not in the genes themselves.

"More startling has been the realization that less than 5 percent of the genome is used to make proteins at all. Most produce a vast range of different factors (RNAs) regulating, through the network, how the other genes are used.

"Increasingly, we are finding that, in complex evolved traits—like human minds—there is little prediction from DNA variation through development to individual differences. The genes are crucial, of course, but nearly all genetic variations are dealt with in the way you can vary your journey from A to B: by constructing alternative routes. “Multiple alternative pathways … are the rule rather than the exception,” reported a paper in the journal BioSystems in 2007.

"Conversely, it is now well known that a group of genetically identical individuals, reared in identical environments—as in pure-bred laboratory animals—do not become identical adults. Rather, they develop to exhibit the full range of bodily and functional variations found in normal, genetically-variable, groups. In a report in Science in 2013, Julia Fruend and colleagues observed this effect in differences in developing brain structures.

"In the same vein, we can now understand why the same genetic resources can be used in many different ways in different organs and tissues. Genes now utilized in the development of our arms and legs, first appeared in organisms that have neither. Genes used in fruit flies for gonad development are now used in the development of human brains. And most genes are used in several different tissues for different purposes at the same time.

"In a paper in Physics of Life Reviews in 2013, James Shapiro describes how cells and organisms are capable of “natural genetic engineering.” That is, they frequently alter their own DNA sequences, rewriting their own genomes throughout life. The startling implication is that the gene as popularly conceived—a blueprint on a strand of DNA, determining development and its variations—does not really exist.

"So it is, in a review in the journal Genetics in 2017, that the geneticists Petter Portin and Adam Wilkins question “the utility of the concept of a basic ‘unit of inheritance’ and the long implicit belief that genes are autonomous agents.” They show that “the classic molecular definition [is] obsolete.'”

Comment: Goodbye Dawkins' Selfish Gene. Shapiro's work on bacteria surely shows how embryology must work, a wild concert of genes, structural forces, hormones and transcriptional distortions all arriving somehow as a reproduced organism. What has been obvious to me is that we have not found an underlying informational control mechanism. It is still a black box, but somehow a massive set of continues coordinated processes produce an emergence of living beings. And it had to be designed, which, obviously, the author does not believe. Again please review comments. They are very thoughtful, especially as they bring information agreeing and disagreeing.