Charting a landmark-driven path forward for population genetics and ancient DNA research in Africa.

Population history-focused DNA and ancient DNA (aDNA) research in Africa has dramatically increased in the past decade, enabling increasingly fine-scale investigations into the continent's past. However, while international interest in human genomics research in Africa grows, major structural barriers limit the ability of African scholars to lead and engage in such research and impede local communities from partnering with researchers and benefitting from research outcomes. Because conversations about research on African people and their past are often held outside Africa and exclude African voices, an important step for African DNA and aDNA research is moving these conversations to the continent. In May 2023 we held the DNAirobi workshop in Nairobi, Kenya and here we synthesize what emerged most prominently in our discussions. We propose an ideal vision for population history-focused DNA and aDNA research in Africa in ten years' time and acknowledge that to realize this future, we need to chart a path connecting a series of "landmarks" that represent points of consensus in our discussions. These include effective communication across multiple audiences, reframed relationships and capacity building, and action toward structural changes that support science and beyond. We concluded there is no single path to creating an equitable and self-sustaining research ecosystem, but rather many possible routes linking these landmarks. Here we share our diverse perspectives as geneticists, anthropologists, archaeologists, museum curators, and educators to articulate challenges and opportunities for African DNA and aDNA research and share an initial map toward a more inclusive and equitable future.

Northeast African genomic variation shaped by the continuity of indigenous groups and Eurasian migrations.

Northeast Africa has a long history of human habitation, with fossil-finds from the earliest anatomically modern humans, and housing ancient civilizations. The region is also the gate-way out of Africa, as well as a portal for migration into Africa from Eurasia via the Middle East and the Arabian Peninsula. We investigate the population history of northeast Africa by genotyping ~3.9 million SNPs in 221 individuals from 18 populations sampled in Sudan and South Sudan and combine this data with published genome-wide data from surrounding areas. We find a strong genetic divide between the populations from the northeastern parts of the region (Nubians, central Arab populations, and the Beja) and populations towards the west and south (Nilotes, Darfur and Kordofan populations). This differentiation is mainly caused by a large Eurasian ancestry component of the northeast populations likely driven by migration of Middle Eastern groups followed by admixture that affected the local populations in a north-to-south succession of events. Genetic evidence points to an early admixture event in the Nubians, concurrent with historical contact between North Sudanese and Arab groups. We estimate the admixture in current-day Sudanese Arab populations to about 700 years ago, coinciding with the fall of Dongola in 1315/1316 AD, a wave of admixture that reached the Darfurian/Kordofanian populations some 400-200 years ago. In contrast to the northeastern populations, the current-day Nilotic populations from the south of the region display little or no admixture from Eurasian groups indicating long-term isolation and population continuity in these areas of northeast Africa.

Case report: Homozygous variants of NEB and KLHL40 in two Arab patients with nemaline myopathy.

Objective: Nemaline myopathies are a heterogeneous group of congenital myopathies caused by mutations in different genes associated with the structural and functional proteins of thin muscular filaments. Most patients have congenital onset characterized by hypotonia, respiratory issues, and abnormal deep tendon reflexes, which is a phenotype encountered in a wide spectrum of neuromuscular disorders. Whole-exome sequencing (WES) contributes to a faster diagnosis and facilitates genetic counseling. Methods: Here, we report on two Arab patients from consanguineous families diagnosed with nemaline myopathy of different phenotype spectrum severities. Results: Clinical assessment and particular prenatal history raised suspicion of neuromuscular disease. WES identified homozygous variants in NEB and KLHL40. Muscle biopsy and muscle magnetic resonance imaging studies linked the genetic testing results to the clinical phenotype. The novel variant in the NEB gene resulted in a classical type 2 nemaline myopathy, while the KLHL40 gene variant led to a severe phenotype of nemaline myopathy, type 8. Both patients were identified as having other gene variants with uncertain roles in their complex phenotypes. Conclusions: This study enriches the phenotypic spectrum of nemaline myopathy caused by NEB and KLHL40 variants and highlights the importance of detailed prenatal, neonatal, and infancy assessments of muscular weakness associated with complex systemic features. Variants of uncertain significance in genes associated with nemaline myopathy may be correlated with the phenotype. Early, multidisciplinary intervention can improve the outcome in patients with mild forms of nemaline myopathies. WES is essential for clarifying complex clinical phenotypes encountered in patients from consanguineous families. Targeted carrier screening of extended family members would enable accurate genetic counseling and potential genetic prevention.

Molecular cytogenetic and phenotypic characterization of Phelan McDermid and 22q13 duplication syndrome: a case report.

BACKGROUND: Phelan-McDermid syndrome (PHMDS) is a rare genetic disorder mostly caused by haploinsufficincy of SHANK3 gene, and characterized by neonatal hypotonia, developmental delay, minor dysmorphic features, seizures and behavior problems. Literature of this syndrome is scanty and confusing, and represents a challenge for pediatricians, in terms of finding the correct diagnoses. CASE PRESENTATION: In a postnatal case with hypotonia and dysmorphic features a de novo ring chromosome r(22) leading to in parallel microdeletion and micro duplication in 22q13 was diagnosed by banding cytogenetics, and further characterized in detail by molecular cytogenetic and chromosomal microarray. CONCLUSION: Here a rare PHMDS case caused by a r(22) is presented. Less than 10 comparable cases are reported in the literature. The present case highlights the importance of conducting genetic counseling and appropriate genetic tests for newborns with mild dysmorphic features.

Case Report: Stem cell therapy in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease leading to loss of upper and lower motor neurons at both spinal and bulbar levels.   For patients with ALS rehabilitation is important to maintain functional independence, ensure safety and optimize quality of life but is not curative. Stem cell therapy (SCT) provides a new approach to treat previously incurable diseases although peer reviewed published evidence has shown no benefit in ALS for slowing disease progression or functional loss.   This case report presents a patient with ALS who underwent SCT but deteriorated rapidly after the procedure. Whether the deterioration was due to the natural progress of the disease or expedited by SCT remains unknown. The ethical considerations of how marketing influences healthcare and individuals' decisions in desperate situations along with reasons for taking desperate measures are discussed.  Patient education and open communication with ALS patients are imperative in gaining patient satisfaction and overcoming ill effects that marketing could have on unconventional methods of intervention. Raising awareness about the availability and access to multidisciplinary care, the timing of decisions with regards to symptom management and end of life care have proven to enhance the quality of life for such patients.

Analysis of HLA gene polymorphisms in East Africans reveals evidence of gene flow in two Semitic populations from Sudan.

Sudan, a northeastern African country, is characterized by high levels of cultural, linguistic, and genetic diversity, which is believed to be affected by continuous migration from neighboring countries. Consistent with such demographic effect, genome-wide SNP data revealed a shared ancestral component among Sudanese Afro-Asiatic speaking groups and non-African populations, mainly from West Asia. Although this component is shared among all Afro-Asiatic speaking groups, the extent of this sharing in Semitic groups, such as Sudanese Arab, is still unknown. Using genotypes of six polymorphic human leukocyte antigen (HLA) genes (i.e., HLA-A, -C, -B, -DRB1, -DQB1, and -DPB1), we examined the genetic structure of eight East African ethnic groups with origins in Sudan, South Sudan, and Ethiopia. We identified informative HLA alleles using principal component analysis, which revealed that the two Semitic groups (Gaalien and Shokrya) constituted a distinct cluster from the other Afro-Asiatic speaking groups in this study. The HLA alleles that distinguished Semitic Arabs co-exist in the same extended HLA haplotype, and those alleles are in strong linkage disequilibrium. Interestingly, we find the four-locus haplotype "C*12:02-B*52:01-DRB1*15:02-DQB1*06:01" exclusively in non-African populations and it is widely spread across Asia. The identification of this haplotype suggests a gene flow from Asia, and likely these haplotypes were brought to Africa through back migration from the Near East. These findings will be of interest to biomedical and anthropological studies that examine the demographic history of northeast Africa.

Y-chromosome variation among Sudanese: restricted gene flow, concordance with language, geography, and history.

We study the major levels of Y-chromosome haplogroup variation in 15 Sudanese populations by typing major Y-haplogroups in 445 unrelated males representing the three linguistic families in Sudan. Our analysis shows Sudanese populations fall into haplogroups A, B, E, F, I, J, K, and R in frequencies of 16.9, 7.9, 34.4, 3.1, 1.3, 22.5, 0.9, and 13% respectively. Haplogroups A, B, and E occur mainly in Nilo-Saharan speaking groups including Nilotics, Fur, Borgu, and Masalit; whereas haplogroups F, I, J, K, and R are more frequent among Afro-Asiatic speaking groups including Arabs, Beja, Copts, and Hausa, and Niger-Congo speakers from the Fulani ethnic group. Mantel tests reveal a strong correlation between genetic and linguistic structures (r = 0.31, P = 0.007), and a similar correlation between genetic and geographic distances (r = 0.29, P = 0.025) that appears after removing nomadic pastoralists of no known geographic locality from the analysis. The bulk of genetic diversity appears to be a consequence of recent migrations and demographic events mainly from Asia and Europe, evident in a higher migration rate for speakers of Afro-Asiatic as compared with the Nilo-Saharan family of languages, and a generally higher effective population size for the former. The data provide insights not only into the history of the Nile Valley, but also in part to the history of Africa and the area of the Sahel.

Co-introgression of Y-chromosome haplogroups and the sickle cell gene across Africa's Sahel.

The Sahel that extends from the Atlantic Ocean to the Ethiopian highland is a historical reservoir of Africa's cultures and grandest populations and a known arena of ancient and recent migrations. We are interested in the issue whether such migrations were also carriers of genetic traits and whether this introgression could be associated with population genetic markers. Based on analysis of Y-chromosome haplogroups, we present evidence that the sickle gene, one of the major protective polymorphisms known in malaria, has in fact found its way only recently to the gene pool of the populations in eastern Sahel. We discuss the possible dynamics of the process and give estimates of the age of the introduction of the S allele into eastern Sahel.

Genetic diversity of lactase persistence in East African populations.

BACKGROUND: The expression of lactase which digests lactose from milk in humans is generally lost after weaning, but selected mutations influencing the promoter of the lactase gene have spread into the human populations. This is considered a classical example of gene-culture co-evolution, and several studies suggested that the lactase gene has been under strong directional evolutionary selective pressure in the past 5000 to 10,000 years. RESULTS: In the present study we investigated the distribution of three gene variants leading to lactase persistence in 12 different East African populations as well as one European population. Our results show that with the exception of Copts and Nilotic populations who are fully lactose non-persistent, the majority of populations of East Africa show at least partly lactose persistence, with both ethnic and socio-economic aspects playing an important role in the distribution of genetic variants. In this study, the variants C/G-13907 and T/G-13915, which are the major variants among the nomadic Arabs in the Arabia and Beja of East Africa, showed remarkable frequencies in Sudanese populations, especially those of pastoralists, in line with the historical links and bidirectional migration of nomadic populations between Arabia and East Africa. The C/T-13910 variant, generally associated with European populations is uniquely present among the Fulani. CONCLUSIONS: These data indicate that a combination of socio-economic, ethnic and evolutionary factors converged to shape the genetic structure of lactase persistence in East African populations.

The genetics of East African populations: a Nilo-Saharan component in the African genetic landscape.

East Africa is a strategic region to study human genetic diversity due to the presence of ethnically, linguistically, and geographically diverse populations. Here, we provide new insight into the genetic history of populations living in the Sudanese region of East Africa by analysing nine ethnic groups belonging to three African linguistic families: Niger-Kordofanian, Nilo-Saharan and Afro-Asiatic. A total of 500 individuals were genotyped for 200,000 single-nucleotide polymorphisms. Principal component analysis, clustering analysis using ADMIXTURE, FST statistics, and the three-population test were used to investigate the underlying genetic structure and ancestry of the different ethno-linguistic groups. Our analyses revealed a genetic component for Sudanese Nilo-Saharan speaking groups (Darfurians and part of Nuba populations) related to Nilotes of South Sudan, but not to other Sudanese populations or other sub-Saharan populations. Populations inhabiting the North of the region showed close genetic affinities with North Africa, with a component that could be remnant of North Africans before the migrations of Arabs from Arabia. In addition, we found very low genetic distances between populations in genes important for anti-malarial and anti-bacterial host defence, suggesting similar selective pressures on these genes and stressing the importance of considering functional pathways to understand the evolutionary history of populations.

Genetic variation of TLR2 and TLR4 among the Saudi Arabian population: insight into the evolutionary dynamics of the Arabian Peninsula.

TLR2 and TLR4 genetic variation has been investigated among the Saudis with the aim of gaining further insight into the evolutionary history of the Arabian Peninsula. Two polymorphisms located in the TLR2 gene (Pro631His and Arg753Gln, rs5743704 and rs5743708, respectively), and two (Asp299Gly and Thr399Ile, rs4986790 and rs4986791, respectively), located in the TLR4 gene have been genotyped in 201 unrelated individuals from Saudi Arabia. While the G allele has been fixed in the Arg753Gln (g.2477 G>A) polymorphism, Pro631His (g.2111 C>A) show remarkable frequencies, a polymorphism that until now has been reported exclusively among European populations. The two TLR4 markers analyzed showed moderate frequencies (ranging from 4% to 5%). Considering the reported protective role of these polymorphisms against malaria, the data suggest that the regional variation at these gene loci could have been shaped by both evolutionary infection pressure and bidirectional human migrations in the past. The population admixture may be due to the existence of gene flow from Sub-Saharan Africa and the Levant to the Arabian Peninsula.

Genetic variation and population structure of Sudanese populations as indicated by 15 Identifiler sequence-tagged repeat (STR) loci.

BACKGROUND: There is substantial ethnic, cultural and linguistic diversity among the people living in east Africa, Sudan and the Nile Valley. The region around the Nile Valley has a long history of succession of different groups, coupled with demographic and migration events, potentially leading to genetic structure among humans in the region. RESULT: We report the genotypes of the 15 Identifiler microsatellite markers for 498 individuals from 18 Sudanese populations representing different ethnic and linguistic groups. The combined power of exclusion (PE) was 0.9999981, and the combined match probability was 1 in 7.4 × 1017. The genotype data from the Sudanese populations was combined with previously published genotype data from Egypt, Somalia and the Karamoja population from Uganda. The Somali population was found to be genetically distinct from the other northeast African populations. Individuals from northern Sudan clustered together with those from Egypt, and individuals from southern Sudan clustered with those from the Karamoja population. The similarity of the Nubian and Egyptian populations suggest that migration, potentially bidirectional, occurred along the Nile river Valley, which is consistent with the historical evidence for long-term interactions between Egypt and Nubia. CONCLUSION: We show that despite the levels of population structure in Sudan, standard forensic summary statistics are robust tools for personal identification and parentage analysis in Sudan. Although some patterns of population structure can be revealed with 15 microsatellites, a much larger set of genetic markers is needed to detect fine-scale population structure in east Africa and the Nile Valley.

Distinct, specific IL-17- and IL-22-producing CD4+ T cell subsets contribute to the human anti-mycobacterial immune response.

We investigated whether the proinflammatory T cell cytokines IL-17 and IL-22 are induced by human mycobacterial infection. Remarkably, >20% of specific cytokine-producing CD4(+) T cells in peripheral blood of healthy, mycobacteria-exposed adults expressed IL-17 or IL-22. Specific IL-17- and IL-22-producing CD4(+) T cells were distinct from each other and from Th1 cytokine-producing cells. These cells had phenotypic characteristics of long-lived central memory cells. In patients with tuberculosis disease, peripheral blood frequencies of these cells were reduced, whereas bronchoalveolar lavage fluid contained higher levels of IL-22 protein compared with healthy controls. IL-17 was not detected in this fluid, which may be due to suppression by Th1 cytokines, as PBMC IL-17 production was inhibited by IFN-gamma in vitro. However, Th1 cytokines had no effect on IL-22 production in vitro. Our results imply that the magnitude and complexity of the anti-mycobacterial immune response have historically been underestimated. IL-17- and IL-22-producing CD4(+) T cells may play important roles in the human immune response to mycobacteria.