# Blood groups of Neandertals and Denisova decrypted

Silvana Condemi, Stéphane Mazières, Pierre Faux, Costedoat Caroline, Andres Ruiz-Linares, Pascal Bailly, Jacques Chiaroni

► To cite this version:

Silvana Condemi, Stéphane Mazières, Pierre Faux, Costedoat Caroline, Andres Ruiz-Linares, et al. "Blood groups of Neandertals and Denisova decrypted. Human Evolution - From Fossils to Ancient and Modern Genomes 2021, Nov 2021, virtual conference, United Kingdom." [hal-03517940](https://hal.science/hal-03517940).

HAL Id: hal-03517940

https://hal.science/hal-03517940

Submitted on 8 Jan 2022

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# Blood groups of Neandertals and Denisova decrypted

CONDEMI Silvana¹, MAZIÈRES Stéphane¹, FAUX Pierre¹, COSTEDOAT Caroline¹,
RUIZ-LINARES Andres¹,²,³, BAILLY Pascal¹,⁴, CHIARONI Jacques¹,⁴

<figure><img src="image_1.png" /></figure>

Scan me for data and more!

<figure><img src="image_2.png" /></figure>

1. Aix Marseille Univ, CNRS, EFS, ADES, UMR 7268, Marseille, France

2. Department of Genetics, Evolution and Environment, and UCL Genetics Institute, University College London, London, United Kingdom

3. Ministry of Education Key Laboratory of Contemporary Anthropology and Collaborative Innovation Center of Genetics and Development, School of Life Sciences and Human Phenome Institute, Fudan University, Yangpu District, Shanghai, China,

4. Etablissement Français du Sang PACA-Corse, « Biologie des Groupes Sanguins », Marseille, France

Email: stephane.mazieres@univ-amu.fr

<figure><img src="image_3.png" /></figure>

: @StphaneMazires1

**Background**
* Red cell blood group systems are relevant to transfusion medicine and anthropology
* Sporadic knowledge of their gene variation in archaic populations

**Aims**
* To explore the archaic gene variation of the key blood groups
* To shed light on the late evolutionary history of Neandertal and Denisova

## Selection of the 4 probands

* High coverage

* Low contamination

* Unadmixed

* Few uncalled snps

<figure><img src="image_4.png" /></figure>

Altai Neandertal
Vindija 33.19
Chagyrskaya 8
Denisova 3

## Caution items

* HG19: 5' strand and alignment with blood group Locus Genomic References

* ABO genotype calls : 5 key snps → enzyme activity

<figure><img src="image_5.png" /></figure>

## Key blood group systems and their genes

<table><tr><td>ABO, H, Se (secretor)</td><td>ABO, FUT1, FUT2</td></tr><tr><td>Rh</td><td>RHD, RHCE</td></tr><tr><td>Kell, Kx</td><td>Kell, XK</td></tr><tr><td>Duffy</td><td>DARC</td></tr><tr><td>Kidd</td><td>SLC14A1</td></tr><tr><td>MNS</td><td>GYPB</td></tr><tr><td>Diego</td><td>SLC4A1</td></tr></table>

* RHD and RHCE haplotypes : The Human RhesusBase,

<figure><img src="image_6.png" /></figure>

ERYTHROGENE Updated!

* Key indels: ABO c.261delG, c.1061delC, and RHCE 209bp

* Low-mapped variants : IGV → Mapping Quality threshold

## Allele exploration procedure

Key snps & exons browsing:
*bam & *vcf files

<figure><img src="image_7.png" /></figure>

<figure><img src="image_8.png" /></figure>

Department of
Evolutionary Genetics

* GT:DP:GQ:A:C:G:T:PL & PP

* Mapping quality 25

* Amino-acid changes

<figure><img src="image_9.png" /></figure>

International Society
of Blood Transfusion

* ClinVar Genomic variation as it relates to human health

<figure><img src="image_10.png" /></figure>

ERYTHROGENE Updated!

<figure><img src="image_11.png" /></figure>

## Alleles and inferred phenotypes

## Probable phenotypes from functional genotypes

### Altai Neandertal (130-90 ky)

**ABO** > A¹ (G-BAAA / G-BAAA), **SeSe**
**partial RhD** > RHD*DIII type4 (602G, 733C) / RHD*DIII type4 (602G, 733C)
**partial Rhce** > RHCE*ceEK / RHCE*ce(48C, 410T, 712G)
K- k+, Js(a+, b-) > KEL*02/*02, KEL*06/*06
Fy(a-, b+) > FY*02/*02
Jk(a+, b-) > JK*01/*01
S-, s+ > GYPB*04/*04
Di(a-, b+) > DI*01/*01

### Vindija 33.19 (65-50 ky)

**ABO** > B (delG-AAAA / G-BABB), **Sese** (rs1800028, c.571T, p.191stop)
**partial RhD** > RHD*DIII type4 (602G, 733C) / RHD*DIII type4 (602G, 733C)
**partial Rhce** > RHCE*ceEK / RHCE*ce(48C, 744C, 787G)
K- k+, Js(a+, b-) > KEL*02/*02, KEL*06/*06
Fy(a-, b+) > FY*02/*02
Jk(a+, b-) > JK*01/*01
S-, s+ > GYPB*04/*04
Di(a-, b+) > DI*01/*01

### Chagyrskaya 8 (51-45 ky)

**ABO** : A¹ (delG-AAA / G-BAAA), **sese** (rs1800028, c.571T, p.191stop)
**partial RhD** > RHD*DIII type4 (602G, 733C) / RHD*DIII type4 (602G, 733C)
**partial Rhce** > RHCE*ceEK / RHCE*ce(48C, 410T, 800A)
K- k+, Js(a+, b-) > KEL*02/*02, KEL*06/*06
Fy(a-, b+) > FY*02/*02
Jk(a+, b-) > JK*01/*01
S-, s+ > GYPB*04/*04

### Denisova 3 (76-52 ky)

**ABO** > O¹ (delG-AAAA / delG-AAAA), **Se/se** (c.714A, p.237stop, undescribed)
**RhD** > RHD*D / RH*D(19G, 186T, 410T, 929G)
**Rhce** > RHCE*ce(48C) / RhCE*ce(48C)
K- k+, Js(a-, b+) > KEL*02/*02, KEL*07/*07
Fy(a-, b+) > FY*02/*02
Jk(a+, b-) > JK*01/*01
S-, s+ > GYPB*04/*04
Di(a-, b+) > DI*01/*01

## Highlights

* Presence of the 3 ABO phenotypes

* Non-secretor alleles

* DIII type 4, *ceEK* → sub-Saharan background, → partial D, partial ce (RH:-18)

* Neandertal-specific RHD haplotype

* Denisova : unknown RHD (c.929A>G, Pro310Arg)

* Homozygous at 6 loci: K-k+, Fy(a-b+), Jk(a+b-), S-s+, Di(a-b+)

* Ancestral alleles: DARC (rs12075 "Fyb", c.125A, p.42Asp), SLC4A1 (rs5036 "Memphis", c.166G, p.56Glu), Kel (rs8176038 "Jsᵇ", c.1790T>C, p. 597Pro)

## Evolutionary outcomes

<figure><img src="image_12.png" /></figure>

confidence > = 0.2 and <0.5 (15.7 Kb)
confidence > = 0.5 and <0.9 (4.6 Kb)

<figure><img src="image_13.png" /></figure>

Introgression scan of modern humans in the RHD region

### 1. Consolidation of an African origin

Ancestral forms for RH, Kell, Duffy, Kidd, MNS and Diego

African clusters of RHD, RHCE variants

Absence of the antigen combination RhC, RhE, K, Fya, Jkb and S

### 2. Admixture before expansion towards Oceania

RHD*DIII type4 with c.602G and DUC2 : only 2 cases in Australia & Papua New Guinea

### 3. Genetic signature of environmental pressure

Polymorphism at the ABO level

→ balanced selection

Non-secretor FUT2 snps

→ exposition to « Norovirus-like »

### 4. Neandertal demography at risk

High level of homozygosity

Partial RhD, Rhc and Rhe antigens → risk of hemolytic disease of the foetus and the new born

## Acknowledgments

* Centre de Calcul Intensif d'Aix-Marseille for granting access to its high performance computing resources.

* Céline Bon, Laure Ségurel and the two anonymous reviewers for their fruitful comments.

## References

* Bokelman et al. 2019. A genetic analysis of the Gibraltar Neanderthals. PNAS, 116 (31) 15610-15615

* Meyer et al. A high-coverage genome sequence from an archaic Denisovan individual. Science, 2012; 338(6104):222-6.

* Mafessoni et al. A high-coverage Neandertal genome from Chagyrskaya Cave. Proc Natl Acad Sci U S A. 2020.

* Möller et al. Erythrogene: a database for in-depth analysis of the extensive variation in 36 blood group systems in the 1000 Genomes Project. Blood Advances. 2016; 1(3):240-9.

* Prüfer et al. The complete genome sequence of a Neanderthal from the Altai Mountains. Nature. 2014; 505(7481):43-9.

* Prüfer et al. A high-coverage Neandertal genome from Vindija Cave in Croatia. Science. 2017; 358(6363):655-8.

* Schoeman EM, Roulis EV, Perry MA, Flower RL, Hyland CA. Comprehensive blood group antigen pro- file predictions for Western Desert Indigenous Australians from whole exome sequence data. Transfus- sion. 2019; 59(2):768-78.

* Thorvaldsdottir et al. Integrative Genomics Viewer (IGV): high-performance genomics data visualization and exploration. Brief Bioinform. 2013; 14(2):178-92.

* Wagner & Flegel. The Rhesus Site. Transfus Med Hemother. 2014; 41(5):357-63.

* Yamamoto & Hakomori S. Sugar-nucleotide donor specificity of histo-blood group ABO system. Nature. 1990; 345(6272):229-33.

* Yamamoto & Hakomori S. Sugar-nucleotide donor specificity of histo-blood group A and B transferases is based on amino acid substitutions. J Biol Chem. 1990; 265(31):19257-62.