The surprising (?) conservation of noncoding DNA

We've known for more than half-a-century that a lot of noncoding DNA is functional. Why are some people still surprised? It's a puzzlement.

A paper in Trends in Genetics caught my eye as I was looking for somethng else. The authors review the various functions of noncoding DNA such as regulatory sequences and noncoding genes. There's nothing wrong with that but the context is a bit shocking for a paper that was published in 2021 in a highly respected journal.

Leypold, N.A. and Speicher, M.R. (2021) Evolutionary conservation in noncoding genomic regions. TRENDS in Genetics 37:903-918. [doi: 10.1016/j.tig.2021.06.007]

Humans may share more genomic commonalities with other species than previously thought. According to current estimates, ~5% of the human genome is functionally constrained, which is a much larger fraction than the ~1.5% occupied by annotated protein-coding genes. Hence, ~3.5% of the human genome comprises likely functional conserved noncoding elements (CNEs) preserved among organisms, whose common ancestors existed throughout hundreds of millions of years of evolution. As whole-genome sequencing emerges as a standard procedure in genetic analyses, interpretation of variations in CNEs, including the elucidation of mechanistic and functional roles, becomes a necessity. Here, we discuss the phenomenon of noncoding conservation via four dimensions (sequence, regulatory conservation, spatiotemporal expression, and structure) and the potential significance of CNEs in phenotype variation and disease.

Identifying functional DNA (and junk) by purifying selection

Functional DNA is best defined as DNA that is currently under purifying selection. In other words, it can't be deleted without affecting the fitness of the individual. This is the "maintenance function" definition and it differs from the "causal role" and "selected effect" definitions [The Function Wars Part IX: Stefan Linquist on Causal Role vs Selected Effect].

It has always been difficult to determine whether a given sequence is under purifying selection so sequence conservation is often used as a proxy. This is perfectly justifiable since the two criteria are strongly correlated. As a general rule, sequences that are currently being maintained by selection are ancient enough to show evidence of conservation. The only exceptions are de novo sequences and sequences that have recently become expendable and these are rare.