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Perfect and imperfect views of ultraconserved sequences

Nature Reviews Genetics volume 23, pages 182–194 (2022)Cite this article

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Abstract

Across the human genome, there are nearly 500 ‘ultraconserved’ elements: regions of at least 200 contiguous nucleotides that are perfectly conserved in both the mouse and rat genomes. Remarkably, the majority of these sequences are non-coding, and many can function as enhancers that activate tissue-specific gene expression during embryonic development. From their first description more than 15 years ago, their extreme conservation has both fascinated and perplexed researchers in genomics and evolutionary biology. The intrigue around ultraconserved elements only grew with the observation that they are dispensable for viability. Here, we review recent progress towards understanding the general importance and the specific functions of ultraconserved sequences in mammalian development and human disease and discuss possible explanations for their extreme conservation.

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Fig. 1: Extreme conservation of ultraconserved elements.
Fig. 2: Ultraconserved sequence functions.
Fig. 3: Possible drivers of enhancer ultraconservation.
Fig. 4: Approaches for the identification of extremely conserved non-coding sequences.

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Acknowledgements

D.E.D. and L.A.P. are Weill Neurohub Investigators, and this work was supported by US National Institutes of Health (NIH) grants R01HG003988 (to L.A.P.), UM1HG009421 (to L.A.P. and A.V.), R01MH117106 (to D.E.D.) and R01DE028599 (to A.V.). Research was conducted at the E.O. Lawrence Berkeley National Laboratory and performed under US Department of Energy Contract DE-AC02-05CH11231, University of California.

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  1. Valentina Snetkova

    Present address: Department of Molecular Biology, Genentech, South San Francisco, CA, USA

Authors and Affiliations

  1. Environmental Genomics & Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA

    Valentina Snetkova, Len A. Pennacchio, Axel Visel & Diane E. Dickel

  2. Comparative Biochemistry Program, University of California, Berkeley, CA, USA

    Len A. Pennacchio

  3. US Department of Energy Joint Genome Institute, Berkeley, CA, USA

    Len A. Pennacchio & Axel Visel

  4. School of Natural Sciences, University of California, Merced, Merced, CA, USA

    Axel Visel

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Related links

BRAVO variant browser: https://bravo.sph.umich.edu/freeze5/hg38/

ENCODE: https://www.encodeproject.org/

VISTA Enhancer Browser: https://enhancer.lbl.gov/

Glossary

Comparative genomics

Comparing DNA sequences of different organisms to identify similarities and differences. Unexpectedly high sequence similarities of loci between species indicate conservation due to negative evolutionary selection and, therefore, often pinpoint regions of the genome that have important functions.

‘Ultraconserved’ elements

Originally defined as regions of the human reference genome of at least 200 bp that are perfectly conserved to both the mouse and rat reference genomes, which is the definition used throughout this Review. In the literature, this term has been more broadly used to refer to highly conserved sequences identified using various definitions of conservation and different combinations of species, which we refer to here instead as ‘extremely conserved’ sequences.

Non-coding

The portion of the genome that does not encode proteins. Approximately 98% of the human genome is non-coding.

Coding

The portion of the genome that encodes proteins.

Derived allele frequencies

A derived allele is a variant that occurs to change a sequence from its previous (ancestral) state. The frequency of an allele is the percentage of the allele in a given population, relative to all observed alleles present at a specific site.

Purifying selection

An evolutionary pressure to remove deleterious sequence variants from a population. Also known as negative selection.

Functional redundancy

Two or more genomic elements (for example, genes or enhancers) perform the same function. When one element is removed, the remaining element is sufficient to carry out this function alone.

Ectopic

In the context of this Review, ectopic refers to expression of a gene in an incorrect location. For example, ectopic reporter gene expression can occur as a result of mutating an enhancer linked to the reporter gene or from a reporter transgene integrating into the genome near an active regulatory element.

Synteny

In this Review, this refers to the conservation in ordering of several blocks of sequence between species.

Haploinsufficient

In this Review, this refers to a dominant mutation that alters the expression of a gene such that the remaining wild-type copy of the gene does not produce sufficient quantities of the encoded protein to prevent a phenotypic change.

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Snetkova, V., Pennacchio, L.A., Visel, A. et al. Perfect and imperfect views of ultraconserved sequences. Nat Rev Genet 23, 182–194 (2022). https://doi.org/10.1038/s41576-021-00424-x

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