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Transposable elements shape the evolution of mammalian development

Nature Reviews Genetics volume 22, pages 691–711 (2021)Cite this article

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Abstract

Transposable elements (TEs) promote genetic innovation but also threaten genome stability. Despite multiple layers of host defence, TEs actively shape mammalian-specific developmental processes, particularly during pre-implantation and extra-embryonic development and at the maternal–fetal interface. Here, we review how TEs influence mammalian genomes both directly by providing the raw material for genetic change and indirectly via co-evolving TE-binding Krüppel-associated box zinc finger proteins (KRAB-ZFPs). Throughout mammalian evolution, individual activities of ancient TEs were co-opted to enable invasive placentation that characterizes live-born mammals. By contrast, the widespread activity of evolutionarily young TEs may reflect an ongoing co-evolution that continues to impact mammalian development.

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Fig. 1: Evolution of mammalian live birth coincided with novel TE insertions and the co-evolution and conservation of abundant TE-binding KRAB-ZFPs.
Fig. 2: Species-specific TEs and KRAB-ZFPs promote the rapid evolution of mammalian pre-implantation development.
Fig. 3: Factors that regulate TEs adopted essential roles during early post-implantation development.
Fig. 4: Co-option of TEs and regulatory mechanisms at the maternal–fetal interface.

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Acknowledgements

The Macfarlan laboratory is funded by the National Institutes of Health (NIH) (DIR 1ZIAHD008933) with additional funding through the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) human placenta project. The authors thank L. Robertson, P. Kurbel, C. Simon, M. Almeida and J. Frank, and members of the Macfarlan laboratory as well as the NICHD Genetics and Epigenetics of Development Group, for discussions and critical comments on the manuscript. Special thanks to K. Pfeifer, P. Rocha, J. Thompson, A. Ivanoff, R. Cosby and M. Gauchier as well as the reviewers for their critical feedback. They apologize to those authors not cited due to space constraints.

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  1. The Eunice Kennedy Shriver National Institute of Child Health and Human Development, The National Institutes of Health, Bethesda, MD, USA

    Anna D. Senft & Todd S. Macfarlan

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  1. Anna D. Senft
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Related links

Dfam TE Classification: https://www.dfam.org/classification/

Dfam TE database: https://www.dfam.org/home

Endoderm Explorer (GUI mouse scRNA-seq): https://endoderm-explorer.com/

gnomAD human sequencing data (including pLi): https://gnomad.broadinstitute.org/

Gypsy TE Database (GyDB): http://gydb.org/index.php/Main_Page

Human Gastrulation (GUI human scRNA-seq): http://human-gastrula.net/

Maternal–Fetal interface (GUI human scRNA-seq): https://maternal-fetal-interface.cellgeni.sanger.ac.uk/

Mouse Genome Informatics (MGI): http://www.informatics.jax.org/

Mouse gastrulation (GUI mouse scRNA-seq): https://marionilab.cruk.cam.ac.uk/MouseGastrulation2018/

Pfam protein domain database: https://pfam.xfam.org/

RepeatMasker Genomic Datasets: http://repeatmasker.org/genomicDatasets/RMGenomicDatasets.html

TEToolkit: https://github.com/mhammell-laboratory/TEtranscriptsTEhub (collaborative platform and reference site): https://tehub.org/

Supplementary information

Glossary

Transposable elements

(TEs). Mobile DNA segments present in virtually all domains of life whose remains make up nearly 50% of most mammalian genomes.

Transpose

Pertaining to transposition, which is the process by which transposable elements (TEs) change their genomic position, leading to the description of TEs as ‘jumping genes’.

Krüppel-associated box zinc finger proteins

(KRAB-ZFPs). KRAB domain containing C2H2-type zinc finger proteins that predominantly act as transcriptional repressors of transposable elements (TEs).

C2H2-type zinc finger

One of the most common domains found in the transcription factors of higher eukaryotes consisting of two cysteines and two histidines that coordinate the binding of a zinc ion, most frequently found in an array of repeated fingers encoded by a single exon.

Purifying selection

Preservation of a nucleotide or amino acid sequence by selective removal of mutations that reduce fitness (for example, visible by an excess of synonymous mutations, which conserve protein structure, relative to non-synonymous mutations).

Long terminal repeat

(LTR). A direct repeat that marks the boundaries of LTR retrotransposons that contain regulatory elements and polyadenylation signals that regulate and enable viral transcription. Initially identical LTRs can recombine, giving rise to so-called solo LTRs.

Endogenous retroviruses

(ERVs). Proviral remnants of ancient retroviral infections of the germ line. ERVs encode viral proteins such as envelopes (env), polymerases (pol) and structural proteins (gag) that, in some cases, allow them to exit as viral particles.

Germ line

Cells in an organism that pass on genetic material to the progeny. The germ line comprises egg and sperm cells (germ cells) and their precursors (primordial germ cells).

Amniotes

A clade of tetrapod vertebrates that comprises reptiles, birds and mammals that evolved ~320 million years ago and relies on internal fertilization and novel extra-embryonic tissues to develop on land.

Extra-embryonic tissues

Fetus-derived tissues that support embryonic development but (for the most part) do not give rise to embryonic structures.

Placenta

A temporary, shared organ of embryonic, extra-embryonic and (in eutheria) also maternal origin that allows development inside the mother by mediating nutrient and waste exchange.

Eutheria

Mammals that develop a placenta from three tissues: the maternal decidua as well as the fetal allantois and chorion.

Therian

Live-born mammals that include marsupials and eutheria.

Invasive placenta

A placenta is invasive when it makes direct contact with maternal blood. This is the case in both mouse and humans, as trophectoderm-derived trophoblast giant cells replace maternal endothelial cells to line maternal blood vessels.

Long interspersed elements

(LINEs). Autonomous non-LTR retrotransposons that comprise the largest transposable element (TE) class in human and mice (~22% of total genomic content).

Short interspersed elements

(SINEs). Non-autonomous non-LTR retrotransposons that rely on the long interspersed element (LINE) machinery to mobilize and are abundant in mammalian genomes (~7.5% mouse, ~13.5% human).

SVA

(SINE variable-number tandem-repeat Alu). Hominid-specific chimeric non-autonomous (long interspersed element 1 (L1)-dependent) retroelements with variable copy number (~2,700 copies in humans, with some of them active) that are a composite of short interspersed element (SINE)-R, variable-number tandem-repeat and Alu elements.

Implantation

The process by which eutherian embryos attach to the uterine wall to establish a sustained maternal–fetal interface that maintains pregnancy. Implantation induces an inflammatory response and can be followed by invasion.

Gastrulation

The embryonic process, lasting for ~72 h from days 6 to 8 in mouse development, that specifies somatic cell fates and a subset of extra-embryonic cell types as well as the germ line, after which twins can no longer form.

Co-option

A process by which natural selection repurposes transposable elements (TEs) for host functions.

Long interspersed element 1

(L1; also known as LINE-1). An active mammalian LINE family in mouse and human (representing 17–20% of their genomes).

DNA methylation

Covalent chemical modification in the form of methylation of cytosines at the fifth position (5-methyl-cytosine (5mC)) that in mammals occurs genome wide predominantly at CpG dinucleotides.

DUF3669

A domain of unknown function found in a few ancient Krüppel-associated box zinc finger proteins (KRAB-ZFPs) that may aid in KRAB-ZFP oligomerization.

SCAN

A gag capsid protein-derived domain found in selected ancient Krüppel-associated box zinc finger proteins (KRAB-ZFPs) that mediates protein interactions.

Zinc fingerprint amino acids

Amino acids at positions −1, +2, +3, and +6 of the C2H2 α-helix that are responsible for direct interactions with specific DNA bases, thus determining the specificity of the zinc fingers.

Zygotic genome activation

(ZGA). The process during which transcription from maternal and paternal genomes in the embryo takes over from maternal control. It occurs at the two-cell or four-cell stage in mice and humans, respectively.

MuERV-L

A murine-specific family of long terminal repeat (LTR) retrotransposons that are highly transcribed at zygotic genome activation (ZGA), present in ~1,500 copies. These elements are related to the endogenous retrovirus L (ERV-L) family of retrotransposons found throughout eutherian mammals that include human ERV-L (HERV-L) elements found in ~2,000 copies.

Long non-coding RNAs

(lncRNAs). RNA molecules >200 nucleotides long that do not encode proteins.

Trophectoderm

A mammalian-specific extra-embryonic cell lineage that gives rise to invasive trophoblast giant cells that mediate implantation in eutheria and to the chorion that contributes to all mammalian placentae.

Blastocyst

A thin-walled hollow embryonic structure containing a eutherian-specific inner cell mass, the future embryo and — dependent on its maturation — one or two extra-embryonic cell lineages.

Trophoblast stem cells

(TSCs). Undifferentiated extra-embryonic stem cells isolated from the trophectoderm in the blastocyst or TSCs shortly after implantation that can functionally contribute to placental development when reintroduced into blastocysts.

Enhancers

Non-coding short (typically 100–1,000 bp in length) DNA sequences that act to drive transcription independent of their relative distance, location or orientation to their cognate promoter. Putative enhancers bear histone modifications such as acetylated histone H3 lysine 27 (H3K27ac) and methylated H3 lysine 4 (H3K4me1).

Embryonic stem cells

(ESCs). Pluripotent stem cells derived from the inner cell mass of the blastocyst that can functionally contribute to the germ line and somatic tissues when reintroduced into blastocysts.

Trophoblast giant cells

Heterogeneous, large, polyploid trophectoderm-derived cells that mediate implantation and decidualization but also line maternal blood vessels and produce hormones in the placenta.

RLTR13

Mouse-specific endogenous retroviruses (ERVs) of the ERV-K family (K standing for the lysine tRNA primer used during reverse transcription) with many subfamilies, for example RLTR13D5 (~685 copies) or RLTR13D6 (~790 copies).

Amnion

Extra-embryonic tissue in amniotes that fills with fluid to form a sac that protects the embryo and provides a watery environment for developing on land.

Allantois

An extra-embryonic mesoderm-derived vascularized sac-like structure that allows gas exchange and disposes of liquid waste. It forms part of the eutherian placenta and becomes the umbilical cord.

Chorion

An extra-embryonic tissue that exchanges gases with the environment and originated in amniotes.

Yolk sac

The oldest extra-embryonic tissue in amniotes that originally absorbed nutrients deposited in yolk but has — despite the lack of yolk in eutherian mammals — remained essential for embryonic development, for example for embryonic patterning and blood development.

Extravillous trophoblast cells

Invasive, differentiated human trophoblast cells (equivalent to mouse trophoblast giant cells) that invade deeply into the uterine stroma, where they line and remodel maternal spiral arteries to supply the placenta with maternal blood.

Extra-embryonic endoderm

The precursor tissue of parts of the mammalian yolk sacs and substantial parts of the developing mammalian gut tube and associated endodermal organs. Extra-embryonic endoderm is also important for embryonic patterning and the specification of embryonic cell types, for example the future brain.

Pluripotency

The ability to functionally contribute to all somatic cells and the germ line of an organism that is maintained after implantation until specific cell types and the germ line are specified through gastrulation.

ERV-K

A subfamily of endogenous retroviruses (ERVs) that uses a lysine (K) tRNA that binds to the viral primer binding site to prime reverse transcription. ERV-K elements in mice contain many mobile elements (for example, intracisternal A-type particle (IAP), early transposon (ETn)).

Embryonic carcinoma cells

(EC cells). Malignant pluripotent cells derived from germ cell tumours called teratocarcinomas. Their culture preceded and paved the way for establishing embryonic stem cells (ESCs).

CRISPR activation/interference

Sequence-specific activation or repression of gene expression on the transcriptional level by exploiting the bacterial genetic immune system clustered regularly interspaced short palindromic repeats (CRISPR) pathway with nuclease-dead Cas9 (dCas9) fused to an activation or repression domain.

LTR5HS

Long terminal repeat (LTR) of one of the youngest families of human endogenous retrovirus-K (HERV-K) elements present in ~700 copies in the human genome.

Epigenetic reprogramming

Erasure and remodelling of epigenetic marks, such as DNA methylation and histone modifications, particularly during early development and in the germ line.

Intracisternal A-type particles

(IAPs). A rodent-specific and still actively retrotransposing class of transposable elements (TEs). They are among the most mutagenic long terminal repeat (LTR) retrotransposons in mammals and are present at ~1,000 full-length copies per haploid genome in mice.

Early transposon

(ETn). A type of non-autonomous mouse-specific long terminal repeat (LTR) retrotransposon that is mobilized by related MusD elements. They are called ‘early transposons’ because they are undetectable in differentiated cell lines. They still actively retrotranspose.

P element

A eukaryotic DNA transposon discovered as one of the first transposable elements (TEs) in Drosophila melanogaster.

Host–transposase fusions

(HTFs). Fusion proteins combining DNA transposase and host-derived domains that often originate via alternative splicing.

Somatic cell nuclear transfer

Transfer of a nucleus of an adult somatic cell to an enucleated egg cell. Pioneered in frogs, nuclear transfer can be used to clone animals as it leads to epigenetic reprogramming towards pluripotency.

Genetic drift

Random sampling from parental genomes in the next generation that generates changes in the frequency of existing genetic traits in a population.

Maternal–fetal interface

Sites where the genetically distinct mother and fetus come into indirect contact. It can refer both to the contact of mother and fetus in the functional placenta and to the implantation site.

Chorioallantoic fusion

Fusion between the allantois and the chorion at day 8–9 of mouse development that subsequently allows the vasculature of the allantois to grow into chorion-derived villi to form the labyrinth layer of the placenta.

Syncytiotrophoblast

Multinucleated layers (two in mice, one in humans) in the placenta that are in indirect contact with maternal blood and act as a transport surface.

env

Retroviral gene encoding a cell surface protein that mediates viral–host cell fusion.

gag

Retroviral genes encoding structural proteins of retroviruses that contribute to capsid formation and are essential for infectivity.

pol

Retroviral genes encoding proteins with enzymatic activities required for viral replication (for example, reverse transcriptase), integration and protein cleavage.

sushi-ichi

Long terminal repeat (LTR) retrotransposons of the Ty3/Gypsy class that encode chromodomain integrases, a primer binding site, two open reading frames for gag and pol genes and a polypurine tract.

Labyrinth

The innermost layer of the mouse placenta that is the main site of nutrient and gas exchange and consists of the syncytiotrophoblast and the vascular network.

Spongiotrophoblast

The hormone-secreting, trophectoderm-derived middle layer of the mouse placenta sandwiched between the outer secondary trophoblast giant cells and the inner labyrinth layer with poorly understood, yet essential, functions in pregnancy.

Genomic imprinting

The parent of origin-specific expression of genes that is established during germ-line development and depends on differential DNA methylation of so-called imprinting control regions (ICRs). Canonical imprints solely depend on DNA methylation, whereas non-canonical imprints (prevalent in the placenta) initially depend on maternally inherited repressive histone marks that are replaced by DNA methylation after implantation.

Gynogenetic

Pertaining to gynogenesis, which is development whereby the embryo contains only maternal chromosomes. Biparental, that is diploid, gynogenetic embryos are produced by transplanting pronuclei between one-cell stage embryos to yield two female pronuclei.

Androgenetic

Pertaining to androgenesis, which is development whereby the embryo contains only paternal chromosomes (see gynogenetic).

Parthenogenetically

Pertaining to parthenogenesis, which is reproduction without fertilization (‘virgin birth’). Parthenogenesis is common in invertebrates and plants.

Mammalian apparent LTR retrotransposons

(MaLRs). Non-autonomous mouse-specific endogenous retroviruses (ERVs) that are the most common retroviral elements in the mouse, making up 4.8% of the genome, and are related to mouse and human ERV-L and human long terminal repeat (LTR) transposon-like human element 1 (THE1; an LTR-containing retrotransposon) elements.

AmnSINE1

A short interspersed nuclear element (SINE) family that amplified in the common amniote ancestor ~320 million years ago that has been conserved in ~200–700 copies in mouse and human genomes.

X-chromosome inactivation

The mammalian-specific process of almost complete silencing of one of the two X chromosomes to equalize the sex chromosome dose in female theria.

Decidualization

Changes of the maternal endometrium in preparation for, and during, mammalian pregnancy. It occurs during menstruation in humans, but is induced by pregnancy in mice (where it can also be triggered by uterine injection with mineral oil drops).

Peripheral regulatory T cells

(pTreg cells). A FOXP3-expressing, specialized immunosuppressive T cell lineage generated extrathymically (peripheral). Regulatory T cells are also generated in the thymus (tTreg cells). Regulatory T cells have essential functions in preventing fatal autoimmunity and inflammation and additional roles in metabolism and tissue repair.

Mammalian-wide interspersed repeats

(MIRs). A widespread subfamily of short interspersed nuclear elements (SINEs) that is often conserved in mammals.

Allogeneic

Genetically dissimilar, and hence immunologically incompatible (within a species); for example, major histocompatibility complex (MHC)-mismatched mouse strains. The opposite of syngeneic, which means genetically similar or identical.

Medium reiteration frequency interspersed repeats

(MERs). A loose grouping of diverse types of DNA transposons and retrotransposons. For example, whereas MER20 is a non-autonomous eutherian-specific subfamily of hobo Activator Tam3 (hAT) Charlie DNA transposons (~4,800 mouse and ~16,000 human copies), MER77 (~400 copies in mouse and 1,200 copies in human) and MER39 (~2600 human copies) are endogenous retroviruses (ERVs).

Parturition

The act or process of giving birth.

LTR transposon-like human element 1B

(THE1B). A long terminal repeat (LTR)-containing retrotransposon that colonized anthropoid primates ~50 million years ago and is present in ~20,000 copies in the human genome.

Epistatic

Pertaining to epistasis, which is the genetic phenomenon whereby the effect of a mutation depends on the presence or absence of other mutations.

MT2B2

A mouse-specific long terminal repeat (LTR) of a class 3 endogenous retrovirus (ERV) present in ~15,000 copies.

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Senft, A.D., Macfarlan, T.S. Transposable elements shape the evolution of mammalian development. Nat Rev Genet 22, 691–711 (2021). https://doi.org/10.1038/s41576-021-00385-1

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