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  • Review Article
  • Published:

Paternal contribution: new insights and future challenges

Nature Reviews Genetics volume 6, pages 633–642 (2005)Cite this article

Key Points

  • Although it has been widely accepted that all that fathers essentially contribute to the next generation is half their genome, recent progress in reproductive biology indicates that the paternal contribution has been underestimated.

  • Although early reports of the presence of RNA in ejaculate sperm were rightfully challenged on a technical level, several groups, using different techniques, have now established their presence in human, mouse and plant sperm.

  • The ability to recover RNA from mature sperm reflects their unique packaging on synthesis in the round spermatid, as they are covered with a protective protein coating during the final burst of transcription.

  • Using high-throughput techniques, sperm transcript profiles from normal fertile men have been developed. These sperm transcripts represent a defined subset of those observed in testis. Interestingly, a series of antisense RNAs have also been identified.

  • Transcription factors, RNAs and signalling molecules are often recovered along with preparations of perinuclear theca or nuclear matrix. This confirms the close contact of these factors and structures that function as nuclear organizing centres.

  • PLCZ (phospholipase Cζ) is delivered by the sperm at fertilization, and has an integral role in the cortical reaction and the induction of a series of Ca2+ oscillations. Human and other primate sperm also deliver a centriole, one of the first structures that was shown to be paternally derived.

  • At the first division after fertilization, a gradient of factors is distributed between the two daughter cells. This has been associated with the beginning of cell-fate specification, raising the intriguing possibility that paternally derived factors might also segregate and be required until the activation of the zygotic genome.

  • The recent demonstration that the RNAs are delivered on fertilization has raised important questions concerning their potential functions. To date, several promising candidates have been identified, including an mRNA that encodes PLCZ and an miRNA that might modulate the insulin-like growth factor 2 receptor, IGF2R.

  • Studies of spermatozoal RNAs as diagnostic tools have been successful. They can be used as biomarkers of fertility in the clinic and in forensic science. Other applications are also being explored, including their use as environmental monitoring agents.

Abstract

It has been widely held that all that fathers essentially contribute to the next generation is half their genome. However, recent progress towards understanding biological processes such as sperm maturation and fertilization now indicates that the paternal contribution has been underestimated. To tackle some of the misconceptions surrounding the paternal contribution, the factors that are actually delivered by the sperm at fertilization and their potential developmental functions will be discussed using data from humans and animal models. Although still in their infancy, the practical applications of using sperm RNAs have already emerged in reproductive medicine as markers that are indicative of successful vasectomy. They are also beginning to appear in the forensic sciences and, within the next decade, might appear in the environmental sciences.

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Figure 1: Spermatogenesis.
Figure 2: Ovum fertilization.
Figure 3: An ontology of biological processes that are represented by sperm RNAs.
Figure 4: Delivery of RNAs present in human sperm.

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Acknowledgements

The author gratefully acknowledges the Michigan Economic Development Corporation and the Michigan Technology Tri Corridor, USA, the US National Institutes of Health and the Department of Obstetrics and Gynecology, Wayne State University, USA, for their support of this research programme. I would also like to thank many colleagues who have contributed to these studies and D.R. Armant of Wayne State University and P. Sutovsky of the University of Missouri-Columbia, USA, for their critical review of the manuscript.

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  1. Department of Obstetrics and Gynecology, Center for Molecular Medicine and Genetics, Institute for Scientific Computing, Wayne State University School of Medicine, 275 East Hancock, Detroit, 48201, Michigan, USA

    Stephen A. Krawetz

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DATABASES

Entrez gene

FOXG1B

H19

Igf2

IGF2R

PRM1

PRM2

WNT5A

Omim

cryptorchidism

testicular cancer

Swiss-Prot

CD9

PLCZ

STAT4

FURTHER INFORMATION

Stephen Krawetz's laboratory

Glossary

TRANSITION PROTEIN

The intermediary DNA packaging protein that replaces the histones in preparation for replacement and chromatin condensation by the protamines.

TOROID STRUCTURE

A thick ring-shaped structure that is formed by the layering of the protamine and interconnecting of these bound sheets of DNA through a series of protamine disulphide bonds.

EPIDIDYMIS

An elongated, highly convoluted tubular structure that stores the sperm as they mature along the caput, the corpus and then the cauda region that leads to the vas deferens.

SERTOLI CELLS

Cells found in the seminiferous tubules that support and nurture the sperm cells.

PERINUCLEAR THECA

A proteinaceous case or sheath that encompasses the male germ-cell nucleus.

CAPUT

The upper region or head of the epididymis.

CAUDA

As sperm mature they reach the cauda region of the epididymis that leads to the vas deferens.

HOMOPLASMY

The situation in which the sequence of every copy of mitochondrial DNA within a cell is identical at any given nucleotide position.

HETEROPLASMY

Literally, this is the 'heterogeneity of the cytoplasm'. The situation in which there is a mixture of two (or more) mitochondrial genotypes within a cell.

ZONA PELLUCIDA

The thick glycoprotein coat of the oocyte, which overlies the oocyte plasma membrane.

ACROSOME REACTION

Having achieved capacitation (in other words, fertilization competancy) through the female reproductive tract, the sperm's membrane is destabilized so that it can bind to the zona pellucida of the ovum. To penetrate the zona pellucida, the sperm's acrosome (a large secretory granule) releases its protease store. As the sperm traverse towards the perivitelline space, the anterior surface of its head is removed, revealing the inner acrosomal membrane.

IZUMO

An immunoglobulin-like sperm plasma-membrane protein that is required for sperm–oocyte fusion.

TETRASPANIN FAMILY

A large family of cell-surface proteins that can form complexes with other tetraspanins and/or cell-surface proteins and might regulate cell-surface receptor trafficking.

CENTRIOLES

Cellular organelle pairs that organize the mitotic spindle at opposite sides of the nucleus during cell division.

DIFFERENTIAL DISPLAY

The high-resolution electrophoretic comparison of multiple RNAs, usually as cDNA or PCR products.

SPERMIOGENESIS

The process by which a spermatid differentiates into a mature sperm.

RIBONUCLEOPROTEIN PARTICLES

RNAs coated with various proteins that can both protect the nacent RNA transcript from degradation and/or modulate translation.

ANIMAL POLE

The section of the ovum that contains the nucleus and the majority of the cytoplasm.

TERATOMA OR DERMOID CYST

A structure that develops from a totipotent primary oocyte. Such structures usually contain a wide range of tissues; for example, hair, teeth and bone.

FETAL ORIGINS OF ADULT DISEASE

The hypothesis that events, factors or the intrauterine environment modify the developmental programme to predispose the individual to chronic disease.

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Krawetz, S. Paternal contribution: new insights and future challenges. Nat Rev Genet 6, 633–642 (2005). https://doi.org/10.1038/nrg1654

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