What is a gene?

Now: The Rest of the Genome
by Carl Zimmer

In this jungle of invading viruses, undead pseudogenes, shuffled exons and epigenetic marks, can the classical concept of the gene survive? It is an open question, one that Dr. Prohaska hopes to address at a meeting she is organizing at the Santa Fe Institute in New Mexico next March.

In the current issue of American Scientist, Dr. Gerstein and his former graduate student Michael Seringhaus argue that in order to define a gene, scientists must start with the RNA transcript and trace it back to the DNA. Whatever exons are used to make that transcript would constitute a gene. Dr. Prohaska argues that a gene should be the smallest unit underlying inherited traits. It may include not just a collection of exons, but the epigenetic marks on them that are inherited as well.

These new concepts are moving the gene away from a physical snippet of DNA and back to a more abstract definition. “It’s almost a recapture of what the term was originally meant to convey,” Dr. Gingeras said.

A hundred years after it was born, the gene is coming home.

Genome 2.0: Mountains Of New Data Are Challenging Old Views
by Patrick Barry

This complex interweaving of genes, transcripts, and regulation makes the net effect of a single mutation on an organism much more difficult to predict, Gingeras says.

More fundamentally, it muddies scientists’ conception of just what constitutes a gene. In the established definition, a gene is a discrete region of DNA that produces a single, identifiable protein in a cell. But the functioning of a protein often depends on a host of RNAs that control its activity. If a stretch of DNA known to be a protein-coding gene also produces regulatory RNAs essential for several other genes, is it somehow a part of all those other genes as well?

To make things even messier, the genetic code for a protein can be scattered far and wide around the genome. The ENCODE project revealed that about 90 percent of protein-coding genes possessed previously unknown coding fragments that were located far from the main gene, sometimes on other chromosomes. Many scientists now argue that this overlapping and dispersal of genes, along with the swelling ranks of functional RNAs, renders the standard gene concept of the central dogma obsolete.

Long Live The Gene

Offering a radical new conception of the genome, Gingeras proposes shifting the focus away from protein-coding genes. Instead, he suggests that the fundamental units of the genome could be defined as functional RNA transcripts.

Since some of these transcripts ferry code for proteins as dutiful mRNAs, this new perspective would encompass traditional genes. But it would also accommodate new classes of functional RNAs as they’re discovered, while avoiding the confusion caused by several overlapping genes laying claim to a single stretch of DNA. The emerging picture of the genome “definitely shifts the emphasis from genes to transcripts,” agrees Mark B. Gerstein, a bioinformaticist at Yale University.

Scientists’ definition of a gene has evolved several times since Gregor Mendel first deduced the idea in the 1860s from his work with pea plants. Now, about 50 years after its last major revision, the gene concept is once again being called into question.

Theory Suggests That All Genes Affect Every Complex Trait
by Veronique Greenwood

Over the years, however, what scientists might consider “a lot” in this context has quietly inflated. Last June, Pritchard and his Stanford colleagues Evan Boyle and Yang Li (now at the University of Chicago) published a paper about this in Cell that immediately sparked controversy, although it also had many people nodding in cautious agreement. The authors described what they called the “omnigenic” model of complex traits. Drawing on GWAS analyses of three diseases, they concluded that in the cell types that are relevant to a disease, it appears that not 15, not 100, but essentially all genes contribute to the condition. The authors suggested that for some traits, “multiple” loci could mean more than 100,000. […]

For most complex conditions and diseases, however, she thinks that the idea of a tiny coterie of identifiable core genes is a red herring because the effects might truly stem from disturbances at innumerable loci — and from the environment — working in concert. In a new paper out in Cell this week, Wray and her colleagues argue that the core gene idea amounts to an unwarranted assumption, and that researchers should simply let the experimental data about particular traits or conditions lead their thinking. (In their paper proposing omnigenics, Pritchard and his co-authors also asked whether the distinction between core and peripheral genes was useful and acknowledged that some diseases might not have them.)

What is inheritance?

The original meaning of a gene was simply a heritable unit. This was long before the discovery of DNA. The theory was based on phenotype, i.e., observable characteristics. What they didn’t know and what still doesn’t often get acknowledged is that much gets inherited from parents, especially from the mother. This includes everything from epigenetics to microbiome, the former determining which genes express and how they express while the latter consists of the majority of genetics in the human body. The fetus will also inherit health conditions from the mother, such as malnutrition and stress, viruses and parasites — all of those surely having epigenetic effects and microbiome changes that could get passed on for generations.

Even more interestingly, DNA itself gets passed on in diverse ways. Viruses will snip out sections of DNA and then put them into the DNA of new hosts. Mothers, including surrogate mothers, can gain DNA from the fetuses they carry. And then those mothers can pass that DNA to any fetus she carries after that, which could cause a fetus to have DNA from two fathers. Fetuses can also absorb the DNA from fraternal twins or even entirely absorb the other fetus, forming what is called a chimera. Bone marrow transplantees also become chimeras because they inherit the stem cells for blood cells from the donor, along with inheriting epigentics from the donor. These chimeras could pass this on during a transplantee’s pregnancy.

We hardly know what all that might mean. There is no single heritable unit that by itself does anything. That is not the direct source of causation. A gene only acts as part of DNA within a specific cell and all of that within the entire biological system existing within specific environmental conditions. The most important causal factors are various. What is in DNA only matters to the degree it is expressed, but what determines its expression will also determine how it expresses. Evelyn Keller Fox writes that, “the causal interactions between DNA, proteins, and trait development are so entangled, so dynamic, and so dependent on context that the very question of what genes do no longer makes much sense. Indeed, biologists are no longer confident that it is possible to provide an unambiguous answer to the question of what a gene is. The particulate gene is a concept that has become increasingly ambiguous and unstable, and some scientists have begun to argue that the concept has outlived its productive prime” (The Mirage of a Space between Nature and Nurture, p. 50). Gene expression as seen in phenotype is determined by a complex system of overlapping factors. Talk of genes doesn’t help us much, if at all. And heritability rates tells us absolutely nothing about the details, such as distinguishing what exactly is a gene as a heritable unit and causal factor, much less differentiating that from everything else. As Fox further explains:

“It is true that many authors continue to refer to genes, but I suspect that this is largely due to the lack of a better terminology. In any case, continuing reference to “genes” does not obscure the fact that the early notion of clearly identifiable, particulate units of inheritance— which not only can be associated with particular traits, but also serve as agents whose actions produce those traits— has become hopelessly confounded by what we have learned about the intricacies of genetic processes. Furthermore, recent experimental focus has shifted away from the structural composition of DNA to the variety of sequences on DNA that can be made available for (or blocked from) transcription— in other words, the focus is now on gene expression. Finally, and relatedly, it has become evident that nucleotide sequences are used not only to provide transcripts for protein synthesis, but also for multilevel systems of regulation at the level of transcription, translation, and posttranslational dynamics. None of this need impede our ability to correlate differences in sequence with phenotypic differences, but it does give us a picture of such an immensely complex causal dynamic between DNA, RNA, and protein molecules as to definitely put to rest all hopes of a simple parsing of causal factors. Because of this, today’s biologists are far less likely than their predecessors were to attribute causal agency either to genes or to DNA itself— recognizing that, however crucial the role of DNA in development and evolution, by itself, DNA doesn’t do anything. It does not make a trait; it does not even encode a program for development. Rather, it is more accurate to think of DNA as a standing resource on which a cell can draw for survival and reproduction, a resource it can deploy in many different ways, a resource so rich as to enable the cell to respond to its changing environment with immense subtlety and variety. As a resource, DNA is indispensable; it can even be said to be a primary resource. But a cell’s DNA is always and necessarily embedded in an immensely complex and entangled system of interacting resources that are, collectively, what give rise to the development of traits. Not surprisingly, the causal dynamics of the process by which development unfolds are also complex and entangled, involving causal influences that extend upward, downward, and sideways.” (pp. 50-52)

Even something seemingly as simple as gender is far from simple. Claire Ainsworth has a fascinating piece, Sex redefined (nature.com), where she describes the new understanding that has developed. She writes that, “Sex can be much more complicated than it at first seems. According to the simple scenario, the presence or absence of a Y chromosome is what counts: with it, you are male, and without it, you are female. But doctors have long known that some people straddle the boundary — their sex chromosomes say one thing, but their gonads (ovaries or testes) or sexual anatomy say another. Parents of children with these kinds of conditions — known as intersex conditions, or differences or disorders of sex development (DSDs) — often face difficult decisions about whether to bring up their child as a boy or a girl.”

This isn’t all that rare considering that, “Some researchers now say that as many as 1 person in 100 has some form of DSD.” And, “What’s more, new technologies in DNA sequencing and cell biology are revealing that almost everyone is, to varying degrees, a patchwork of genetically distinct cells, some with a sex that might not match that of the rest of their body. Some studies even suggest that the sex of each cell drives its behaviour, through a complicated network of molecular interactions. Gender should be one of the most obvious areas to prove genetic determinism, if it could be proven. But clearly there is more going on here. The inheritance and expression of traits is a messy process. And we are barely scratching the surface. I haven’t seen any research that explores how epigenetics, microbiome, etc could influence gender or similar developmental results.