Tuesday, January 8, 2019

Susumu Ohno: Accounting for Why Gene Counting Doesn't Account for Things

Gifts, gifts, gifts!  Every day in the media, often promoted by universities, journals, and NIH, we seem to be offered the imminent gift of immortality, if we but pony up for more and more 'omical' science (well, if you have to pay for it, even via taxes, I guess it's not exactly a gift!).

The promise that for nearly two decades has been the main course on the 'omicists' menus, is that by counting--adding up the contributions of a list of enumerated genome locations--all our woes will be gone!  The idea is simple: genes are fundamental to life because they code for proteins and stuff like that, which are the basis of life.  This, in a nutshell, is the justification for much of the Big Data endeavors being sponsored by the NIH these days, long driven for historical reasons by an obsession with genes.

But, at least partly, this obsession has revealed to us what we should--and could--already have known.  Genes are clearly fundamental to life, coding for proteins and other functions.  But the reason we're seeing increasing weariness with GWAS and other fiscally high but scientifically low yield approaches is not new.  It's not secret.  And it is not a surprise.  All we needed to do was to ask, where do genes come from?  It is not a new question, the genome has been intensively studied, and indeed the answer has been known for nearly 50 (that is, fifty) years.

Susumu Ohno (1928-2000), from Google images)
In 1970 Susumu Ohno published his deeply insightful Evolution by Gene Duplication.  This book should be a must-read for all life-science graduate students.  Instead, it has been casually forgotten--one might say conveniently forgotten, except that in our culpable ignorance of the history of our field  or to suit our self-serving careerism, it has not been deemed important to read anything published more than a few years ago.

So, what did Ohno say?

Where do 'genes' come from?
In his time, we didn't have much in the way of DNA sequencing.  We knew that genes coded for proteins, and were located on chromosomes.  We had learned a lot about how the code works, much of this from experiments, such as with bacteria.  We knew proteins were fundamental building blocks of life, and were strings of amino acids.  Watson and Crick and others had shown how DNA carries the relevant code, and so on.

But that did not answer the question: Where do all these genes come from?  I'm not an historian, and cannot claim to know the many threads leading to the answer.  But in essence, a point Ohno is credited for noting and whose importance he stressed, is that new genes largely arise from duplication events affecting existing genes.  He had noticed amino acid similarities among some known proteins (hemoglobins); this and other evidence suggested that chromosomal or individual gene duplication was a mechanism, if not the mechanism, for the origin of new genes.  Expecting random mutations in parts of DNA not already being used to code for RNA or DNA, to generate all the sequence aspects of a code for a new protein that would actually have some use, was too far-fetched.  Indeed, nowadays one can be skeptical if an 'orphan' gene is claimed--that is, one not part of a gene family, of which there are also other genes in the genome.

Instead, if occasionally a stretch of DNA or even a whole chromosome duplicates, the individual inheriting that expanded genome gains two potentially important attributes.  First, s/he has a redundant code; mutational errors in one gene that lead to a non-functional protein can be compensated for by the fact that an entirely different, duplicate gene exists and codes for the same protein.

Secondly, duplication is the basis of a much deeper, indeed fundamental aspect of life, going farther even than just gene: redundancy.

Evolution depends on redundancy: genomes are family affairs
By having redundant genes, the initial result of duplication, an individual is more likely to survive mutations.  And over the long haul, with lots of duplication, the additional copies of a needed gene can mutate and over time take on new function, without threat to the individual, who will still have one or more healthy versions of the gene.

Indeed, perhaps one of the far under-appreciated but even fundamental axioms of life is that it is built on redundancy: not only are genomes almost exclusively carriers of members of gene families whose individual genes arose by duplication events, but our tissues themselves are constructed by repeating fundamental units: multicellular organization generally; bilateral or radial symmetry; blood cells, intestinal villi, lobes and alveoli in lungs, nephrons in kidneys, and so on.

I think it is not easy to imagine a different evolutionary way for our very simple biochemical beginnings to generate the kinds of complex organisms that populate the Earth.  And this has deep consequences for those for whom dreams of omical sugar plums dance in their heads.

Why the 'omics' promises were always doomed to fail, or at least to pale
From the cell theory to Ohno to the very data that our 'omical dreams have yielded in extensive amounts, we have found that life relies on the protection of redundancy.  From genes on up, if one thing goes wrong, there's an ally to pick up the slack.  Redundancy means back-ups and alternatives.  It also provides individual uniqueness, which is also fundamental to the dynamics evolution.

Together, these facts (and they're facts, not just wild speculations) show that, and why, we can't expect to predict everything from individual genes or even gene scores.  There are many roads to the Promised Land.

It is important, I think, and entirely fair to assert that nothing I've said here has ever been secret, known only to a small, Masonic Lodge of biologists exchanging secret handshakes.  Indeed, these basic facts have been at the heart of our science since the advent of the cell theory, centuries ago.  Genomics has largely just added to what was already known as a generalization about life.

The implicit lesson, of Ohmo not Homer, is to Beware of Geneticists Bearing Gifts.

(updated to correct a spelling error in Prof. Ohno's name)

1 comment:

Ken Weiss said...

I should add that the roles of duplicate genes need not be identical, as they can vary in sequence details due to subsequent mutation, they can have varying regulatory regions, and their effects will relate to those of other genes and the results need not be simply additive. There is no Ohno-like role for these aspects of the results of gene duplication.