The X chromosome and sex-specific effects in infectious disease susceptibility

doi:10.1186/s40246-018-0185-z

Review

. 2019 Jan 8;13(1):2.

doi: 10.1186/s40246-018-0185-z.

The X chromosome and sex-specific effects in infectious disease susceptibility

Haiko Schurz^{1

2}, Muneeb Salie³, Gerard Tromp^{4

5}, Eileen G Hoal⁴, Craig J Kinnear⁴, Marlo Möller⁴

Affiliations

¹ DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. haiko@sun.ac.za.
² South African Tuberculosis Bioinformatics Initiative (SATBBI), Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. haiko@sun.ac.za.
³ Department of Genetics, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
⁴ DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
⁵ South African Tuberculosis Bioinformatics Initiative (SATBBI), Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.

PMID: 30621780
PMCID: PMC6325731
DOI: 10.1186/s40246-018-0185-z

Review

The X chromosome and sex-specific effects in infectious disease susceptibility

Haiko Schurz et al. Hum Genomics. 2019.

. 2019 Jan 8;13(1):2.

doi: 10.1186/s40246-018-0185-z.

Authors

Haiko Schurz^{1

2}, Muneeb Salie³, Gerard Tromp^{4

5}, Eileen G Hoal⁴, Craig J Kinnear⁴, Marlo Möller⁴

Affiliations

¹ DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. haiko@sun.ac.za.
² South African Tuberculosis Bioinformatics Initiative (SATBBI), Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. haiko@sun.ac.za.
³ Department of Genetics, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
⁴ DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
⁵ South African Tuberculosis Bioinformatics Initiative (SATBBI), Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.

PMID: 30621780
PMCID: PMC6325731
DOI: 10.1186/s40246-018-0185-z

Abstract

The X chromosome and X-linked variants have largely been ignored in genome-wide and candidate association studies of infectious diseases due to the complexity of statistical analysis of the X chromosome. This exclusion is significant, since the X chromosome contains a high density of immune-related genes and regulatory elements that are extensively involved in both the innate and adaptive immune responses. Many diseases present with a clear sex bias, and apart from the influence of sex hormones and socioeconomic and behavioural factors, the X chromosome, X-linked genes and X chromosome inactivation mechanisms contribute to this difference. Females are functional mosaics for X-linked genes due to X chromosome inactivation and this, combined with other X chromosome inactivation mechanisms such as genes that escape silencing and skewed inactivation, could contribute to an immunological advantage for females in many infections. In this review, we discuss the involvement of the X chromosome and X inactivation in immunity and address its role in sexual dimorphism of infectious diseases using tuberculosis susceptibility as an example, in which male sex bias is clear, yet not fully explored.

Keywords: Host genetics; Sex bias; Susceptibility; Tuberculosis; X chromosome.

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Not applicable for this review.

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Not applicable for this review.

Competing interests

The authors declare that they have no competing interests.

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Figures

**Fig. 1**
Illustration of the X chromosome indicating the five different strata and chances of genes escaping inactivation within each stratum. Regions lined in red contain the highest densities of immune-associated genes while genes discussed in this review are indicated in green. Genes that contain intragenic miRNA are indicated in black followed by the miRNA number. XIC: X chromosome inactivation centre containing *XIST* and *XACT* genes; PAR: Pseudoautosomal region; *TLR8*: Toll-like receptor 8; *TLR7*: Toll-like receptor 7; *CYBB*: Cytochrome b-245, beta polypeptide; AR: Androgen receptor; *CXCR3*: C–X–C motif chemokine receptor 3; *TNFS5*: Encodes CD40 ligand; *NEMO*: NF-kB essential modulator; *IRAK1*: Interleukin-1 receptor associated kinase 1; *HUWE1*: HECT, UBA & WWE domain containing 1; *GABRA3*: Gamma-aminobutyric acid A receptor subunit alpha 3

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References

1. Balaton BP, Dixon-McDougall T, Peeters SB, Brown CJ. The eXceptional nature of the X chromosome. Hum Mol Genet. 2018;27(R2):R242–R249. doi: 10.1093/hmg/ddy148. - DOI - PMC - PubMed
1. Hughes JF, Page DC. The biology and evolution of mammalian Y chromosomes. Annu Rev Genet. 2015;49:507–527. doi: 10.1146/annurev-genet-112414-055311. - DOI - PubMed
1. Lahn BT, Page DC. Four evolutionary strata on the human X chromosome. Science. 1999;286(5441):964–967. doi: 10.1126/science.286.5441.964. - DOI - PubMed
1. Chromosome X: 1-1 - Chromosome summary - Homo sapiens - Ensembl genome browser 88 [Internet]. [cited 2018 Oct 22]. Available from: http://mar2017.archive.ensembl.org/Homo_sapiens/Location/Chromosome?r=X
1. Gao F, Chang D, Biddanda A, Ma L, Guo Y, Zhou Z, et al. XWAS: a software toolset for genetic data analysis and association studies of the X chromosome. J Hered. 2015;106(5):666–671. doi: 10.1093/jhered/esv059. - DOI - PMC - PubMed

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[1] Balaton BP, Dixon-McDougall T, Peeters SB, Brown CJ. The eXceptional nature of the X chromosome. Hum Mol Genet. 2018;27(R2):R242–R249. doi: 10.1093/hmg/ddy148. - DOI - PMC - PubMed

[2] Balaton BP, Dixon-McDougall T, Peeters SB, Brown CJ. The eXceptional nature of the X chromosome. Hum Mol Genet. 2018;27(R2):R242–R249. doi: 10.1093/hmg/ddy148. - DOI - PMC - PubMed

[3] Hughes JF, Page DC. The biology and evolution of mammalian Y chromosomes. Annu Rev Genet. 2015;49:507–527. doi: 10.1146/annurev-genet-112414-055311. - DOI - PubMed

[4] Hughes JF, Page DC. The biology and evolution of mammalian Y chromosomes. Annu Rev Genet. 2015;49:507–527. doi: 10.1146/annurev-genet-112414-055311. - DOI - PubMed

[5] Lahn BT, Page DC. Four evolutionary strata on the human X chromosome. Science. 1999;286(5441):964–967. doi: 10.1126/science.286.5441.964. - DOI - PubMed

[6] Lahn BT, Page DC. Four evolutionary strata on the human X chromosome. Science. 1999;286(5441):964–967. doi: 10.1126/science.286.5441.964. - DOI - PubMed

[7] Chromosome X: 1-1 - Chromosome summary - Homo sapiens - Ensembl genome browser 88 [Internet]. [cited 2018 Oct 22]. Available from: http://mar2017.archive.ensembl.org/Homo_sapiens/Location/Chromosome?r=X

[8] Chromosome X: 1-1 - Chromosome summary - Homo sapiens - Ensembl genome browser 88 [Internet]. [cited 2018 Oct 22]. Available from: http://mar2017.archive.ensembl.org/Homo_sapiens/Location/Chromosome?r=X

[9] Gao F, Chang D, Biddanda A, Ma L, Guo Y, Zhou Z, et al. XWAS: a software toolset for genetic data analysis and association studies of the X chromosome. J Hered. 2015;106(5):666–671. doi: 10.1093/jhered/esv059. - DOI - PMC - PubMed

[10] Gao F, Chang D, Biddanda A, Ma L, Guo Y, Zhou Z, et al. XWAS: a software toolset for genetic data analysis and association studies of the X chromosome. J Hered. 2015;106(5):666–671. doi: 10.1093/jhered/esv059. - DOI - PMC - PubMed

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The X chromosome and sex-specific effects in infectious disease susceptibility

Affiliations

The X chromosome and sex-specific effects in infectious disease susceptibility

Authors

Affiliations

Abstract

Conflict of interest statement

Ethics approval and consent to participate

Consent for publication

Competing interests

Publisher’s Note

Figures

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Cited by

References

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Abstract

Conflict of interest statement

Ethics approval and consent to participate

Consent for publication

Competing interests

Publisher’s Note

Figures

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