Closing the Gaps in Genomic Research

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SRY by selﬁsh alleles at other loci. A speciﬁc candidate is the so-called ‘feminizing X’

allele found in various rodents [2]. Feminiz- ing X alleles cause XY individuals to develop as females, thereby gaining an advantage through an ingenious strategy: in crosses with standard XY males, feminized XY females produce one-fourth nonviable YY progeny, leading to two-thirds of surviving progeny inheriting the feminizing X allele [2]. Suppression of the ancestral SRY masculinizing function could have se- lected for acquisition of the novel spong- ing poly-CAG region, despite the costs of the coincidentally acquired destabilizing degron region.

The extent to which intragenomic conflict drives the evolution of seemingly costly traits, such as the degron of SRY, remains an open question. In addition to the Aristote- lian–Darwinian presumption that biological features exist because they enhance the function (orfitness) of the individual, it has increasingly been appreciated that other features may arise or persist because selection is simply too weak to effectively op- pose them [9]. Intragenomic conflict offers a third possibility: namely, that a feature at one locus may be beneficial despite some costs if it also helps the locus to escape manipulation by selfish alleles at another locus. A particularly promising avenue for in- vestigation is considering the wealth of ro- dent novelties of sex determination in the context of potentially age-old arms races between feminizing X alleles and re- pressed Y chromosomes, consistent with the notion that intragenomic conflict may have important roles in the origins of novel genetic systems [10].

Miyawaki et al. have broken new ground in our understanding of the diversity and function of the ancient mammalian sex determination system. The past years have seen an explosion of information on the genetic sex determination mechanisms of animals, plants, and fungi, and it will be

fascinating to learn more about the alterna- tive forms and mechanisms of action of these crucial genes.

Acknowledgments

I thank Noelle Anderson and Polly Campbell for thoughtful comments on an early draft of the manuscript.

1San Francisco State University, 1600 Holloway Ave, San Francisco, CA 94132, USA

*Correspondence:

scottwroy@gmail.com(S.W. Roy).

https://doi.org/10.1016/j.tig.2020.11.004

References

1. Waters, P.D. et al. (2007) Mammalian sex: origin and evolution of the Y chromosome and SRY. Semin. Cell Dev. Biol. 18, 389–400

2. Burt, A. et al. (2009) Genes in Conﬂict: The Biology of Selﬁsh Genetic Elements, Harvard University Press 3. Zhao, L. et al. (2014) Structure–function analysis of mouse

Sry reveals dual essential roles of the C-terminal polyglutamine tract in sex determination. Proc. Natl.

Acad. Sci. U. S. A. 111, 11768–11773

4. Miyawaki, S. et al. (2020) The mouse Sry locus harbors a cryptic exon that is essential for male sex determination.

Science 370, 121–124

5. Hansen, T.B. et al. (2013) Natural RNA circles function as efﬁcient microRNA sponges. Nature 495, 384–388 6. Liu, Y. et al. (2016) miR-138 suppresses cell proliferation and

invasion by inhibiting SOX-9 in hepatocellular carcinoma.

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7. Sha, H.H. et al. (2017) MiR-138: a promising therapeutic target for cancer. Tumor Biol. 39 p.1010428317697575 8. Lundrigan, B.L. and Tucker, P.K. (1997) Evidence for

multiple functional copies of the male sex-determining locus, Sry, in African murine rodents. J. Mol. Evol. 45, 60–65

9. Lynch, M. and Walsh, B. (2007) The Origins of Genome Architecture, Sinauer Associates

10. Ross, L. et al. (2010) Genomic conﬂict in scale insects: the causes and consequences of bizarre genetic systems.

Biol. Rev. 85, 807–828

Spotlight

Closing the Gaps in Genomic Research

Cesar Fortes-Lima

^1,

* and Carina Schlebusch

^1,2,3,

*

Despite Africa’s central role in the origin of our species, our knowledge

of the genomic diversity in Africa is remarkably sparse. A recent publi- cation by Choudhuryet al. under- scores the scientiﬁc imperative for a broader characterisation of African genomic diversity to better understand demographic history and improve global human health.

Human populations are known to harbour the greatest genetic diversity in Africa, from where modern humans originated. There- fore, studying genomic patterns of diversity in Africa presents remarkable opportunities to gain a better understanding about our deep population history and the underlying genetic basis of human adaptation and disease [1]. However, in comparison to populations of European or Asian ancestry, African populations are largely under- represented in genomic research, exac- erbating health inequalities [2]. Heavily bi- ased genetic databases often lead scientists and medical doctors to diag- nose conditions or prescribe treatments that might be relevant to people with European ancestry, but not for people from other genetic backgrounds. To investi- gate the genomic diversity across the African continent, a recent paper by Choudhury et al. [3] analysed whole- genome sequencing data of 426 individuals representing 50 ethnolinguistic groups in Africa (Figure 1). This ground-breaking study represents an important step in ad- dressing existing biases in available data for genetic research, which hamper the study of human health problems in populations from Africa and the African Diaspora.

The study was led by the Human Heredity and Health in Africa (H3Africa) Consortiumⁱ [4], funded by the US National Institutes of Health (NIH) and the Wellcome Sanger Institute, to redress the long-standing scarcity of genomic research in African populations and to support African institu- tions conducting genomic research. The high coverage of the newly available

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Trends Trends inin GeneticsGenetics

Figure 1. Geographical Locations of African Populations Included in the Human Heredity and Health in Africa (H3Africa) Dataset De- scribed by Choudhury et al. [3] and from Pub- licly Available Data.Dots are proportional to sample sizes of populations. Red dots show African populations included in the 1000 Genomes Project Phase 3.

The map shows the distri- bution of frequencies for the APOL1 risk genotype in Africa that were estimated by Choudhury et al.

[3]. Geographical gradients were estimated here using the Kriging method and on the basis of cumulative frequencies of APOL1* geno- types (G1 homozygotes, G2 homozygotes, or G1G2 heterozygotes).

African genomes (with an average depth of coverage between 10x and 30x) allowed the authors to better examine rare genetic variants in an accurate and quantifiable way. Choudhury et al. [3] uncovered more than three million novel variants, mostly found in newly sampled ethnolinguistic groups from Botswana and Mali (over 18 700 and 13 300 novel variants per individual, respectively) and identified 33 loci with strong evidence of selection that have not been reported previously in African [5] or world-wide populations [6]. As expected, the results reflected the long history and rich genomic diversity across the continent and further evidenced the enormous scope for identifying novel variants in future genomic studies in Africa.

This is one of the largest studies of high- depth-sequenced African genomes reported to date, and samples were analysed from 13 African countries (Figure 1); however, coverage remains notably

incomplete in some African regions. Cer- tain ethnolinguistic groups that are crucial for population history inferences were not included in this study, such as hunter– gatherer groups, whose genetic heritage represents early (prefarming) African history, due to their deep continuities in their respec- tive regions. This poses an important limita- tion for producing accurate inferences regarding deep population history and his- torical mass migration in Africa and future research will need to include more geographically and linguistically diverse populations to be able to test different hypothe- ses. For instance, Southern African hunter– gatherers (San) and herders (Khoekhoe), known collectively as Khoe-San speaking people, have more genomic diversity than other African and non-African groups and represent the deepest population diver- gence within Homo sapiens, supported by a recent study [7] of high-coverage whole- genomes of ﬁve Khoe-San populations (with an average depth of coverage 50x).

Likewise, hunter–gatherer groups from the

Central African rainforest and East Africa are other crucial populations to include in future genomic studies [8].

Long-distance migrations played a pivotal role in shaping the genomic landscape in the African continent, particularly migrations of people speaking Bantu languages. The broad dispersion of Bantu-speaking people has been ascribed to a series of migrations across sub-Saharan Africa over the past 5000 years, supported by genome-wide studies [9,10]. Choudhury et al. [3] observed complex genomic patterns of ancestral mixing within and between populations and suggested that Zambia was a likely interme- diate site along the routes of expansion of Bantu-speaking populations to both East and South Africa. However, thesefindings need to be interpreted with caution and more Bantu-speaking populations representing South, East, and Central Africa will be needed to confirm and refine these findings, as well as the use of haplotype-based methods, model-testing approaches, and well-defined hypothesis- driven research. The Bantu-expansion was likely a complex movement of multiple waves of populations interacting with and replacing each other [1] and fine-scale data from modern and ancient individuals across sub-Saharan Africa will be crucial to disentangle the complex history behind this huge expansion.

In order to generalise the discoveries from genetic studies of complex diseases and to provide opportunities for new understanding of disease aetiology and potential therapeutic strategies, it is crucial to inves- tigate genetic variation in world-wide populations, particularly in non-European populations. The study by Choudhury et al. [3] contributes signiﬁcantly to an increasingly global context of medically relevant genetic variation and uncovers the genomic landscape of loci associated with chronic noncommunicable diseases in Africa (e.g., cardiometabolic diseases).

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Furthermore, it facilitates future studies exploring the relevance of genetic variants in disease burden among the African populations. An example is the APOL1 variants (Figure 1) that provide protection against speciﬁc Trypanosoma species in African populations from endemic regions like West Africa, but also increase susceptibility to nephropathy in populations from non-trypanosomiasis endemic areas in Africa or from the African Diaspora.

The study also identiﬁes new evidence for natural selection in 62 genes associated with immune-related functions (for viral and bacterial infection), involved in DNA maintenance and carbohydrate and lipid metabolism. The researchers additionally teased out signals of selection within each population, for example, genes involved in metabolism were under selection among individuals from Botswana.

Among the selection signals detected in Botswana, the authors also found evidence for preferential gene-ﬂow from Khoe-San ancestry, highlighting adaptive introgression in Southern Africa.

The study presented by Choudhury et al.

[3] is also a major milestone in African genomics research capacity, as it was led predominantly by local researchers using local infrastructure and resources for large-scale genomics research in Africa.

Collectively, their results reﬁne our current understanding of human migration, patterns of admixture, and strong drivers of selection across the African continent.

The study also points out the extent of uncatalogued genomic variation across the continent and the need for future genomic studies of the many diverse under-represented populations in Africa.

Acknowledgements

C.F-L. and C.S. were funded by the European Research Council (ERC StG AfricanNeo, grant no. 759933 to C.S.).

C.F-L. was funded by the Marcus Borgström Founda- tion for Genetic Research, the Sven and Lilly Lawski's Foundation, and the Royal Physiographic Society of Lund (Nilsson-Ehle Endowments).

Resources

ihttps://h3africa.org/

1Human Evolution, Department of Organismal Biology, Evolutionary Biology Centre, Uppsala, Sweden

2Palaeo-Research Institute, University of Johannesburg, Johannesburg, South Africa

3SciLifeLab, Uppsala, Sweden

*Correspondence:

cesar.fortes-lima@ebc.uu.se(C. Fortes-Lima) and carina.schlebusch@ebc.uu.se(C. Schlebusch).

https://doi.org/10.1016/j.tig.2020.11.005

creativecommons.org/licenses/by-nc-nd/4.0/).

References

1. Schlebusch, C.M. and Jakobsson, M. (2018) Tales of human migration, admixture, and selection in Africa.

Annu. Rev. Genomics Hum. Genet. 19, 405–428 2. Sirugo, G. et al. (2019) The missing diversity in human

genetic studies. Cell 177, 1080

3. Choudhury, A. et al. (2020) High-depth African genomes inform human migration and health. Nature 586, 741–748 4. H3Africa Consortium et al. (2014) Research capacity. Enabling the genomic revolution in Africa. Science 344, 1346–1348 5. Gurdasani, D. et al. (2019) Uganda genome resource

enables insights into population history and genomic discovery in Africa. Cell 179, 984–1002

6. Bergström, A. et al. (2020) Insights into human genetic variation and population history from 929 diverse genomes. Science 367, eaay5012

7. Schlebusch, C.M. et al. (2020) Khoe-San genomes reveal unique variation and conﬁrm the deepest population diver- gence in Homo sapiens. Mol. Biol. Evol. 37, 2944–2954 8. Fan, S. et al. (2019) African evolutionary history inferred

from whole genome sequence data of 44 indigenous African populations. Genome Biol. 20, 82

9. Patin, E. et al. (2017) Dispersals and genetic adaptation of Bantu-speaking populations in Africa and North America.

Science 356, 543–546

10. Semo, A. et al. (2020) Along the Indian Ocean coast: genomic variation in Mozambique provides new insights into the Bantu expansion. Mol. Biol. Evol. 37, 406–416

Science & Society

Genetics and COVID-19:

How to Protect the Susceptible

Robert I. Field,

¹

Anthony W. Orlando ,

^2,

* and Arnold J. Rosoff

³

Along with the potential for break- throughs in care and prevention, the search for genetic mechanisms

underlying the spread and severity of coronavirus disease 2019 (COVID- 19) introduces the risk of discrimination against those found to have markers for susceptibility. We pro- pose new legal protections to miti- gate gaps in protections under existing laws.

Genetic research holds the promise of unlocking secrets of COVID-19 and opening new avenues for mitigation [1].

Among suggestiveﬁndings to date is a possible correlation between disease severity and DNA polymorphisms in the virus host factors ACE2 and TMPRSS2 [2]. Findings on genetic correlates of COVID-19 progression may lead to better understanding of the cellular mechanisms of susceptibility and resistance and may enable predictions of individual risk for severe disease progression.

Discrimination Risks

However, such advances come with a signiﬁcant social risk in the potential for a new form of discrimination. Until a vac- cine or effective treatment is available, those whose genomes make them especially vulnerable might be considered ill-suited for exposure-prone jobs, especially in health care. They might also face resistance in other spheres, such as health- related insurance, apartment leases, nursing home placements, and even bank loans. Conversely, those found to have genetic resistance may be treated more favorably in these regards.

Governments would also face incentives to favor those with genetic resistance to COVID-19 in disease mitigation strategies.‘Genetic passports’ exempting ge- netically resistant individuals from strict social distancing restrictions would enable states to avoid more widespread lockdowns. Those with genetic markers for susceptibility would face stronger restrictions.

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