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The optokinetic reflex (OKR) serves as a vital index for visual system development in early life, commonly observed within the first six months post-birth in humans. Zebrafish larvae offer a robust and convenient model for OKR studies due to their rapid development and manageable size. Existing OKR assays often involve cumbersome setups and offer limited portability. In this study, we present an innovative OKR assay that leverages the flexible screen of the Samsung Galaxy Z Flip to optimize setup and portability. We conducted paired slow-phase velocity measurements in 5-day post-fertilization (dpf) zebrafish larvae (n = 15), using both the novel flip-phone-based assay and a traditional liquid-crystal display (LCD) arena. Utilizing Bland-Altman plots, we assessed the agreement between the two methods. Both assays were efficacious in eliciting OKR, with eye movement analysis indicating high tracking precision in the flip-phone-based assay. No statistically significant difference was observed in slow-phase velocities between the two assays (p = 0.40). Our findings underscore the feasibility and non-inferiority of the flip-phone-based approach, offering streamlined assembly, enhanced portability, and the potential for cost-effective alternatives. This study contributes to the evolution of OKR assay methodologies, aligning them with emerging research paradigms., (© 2024. The Author(s).)

Amblyopia is an important public health concern. While home-based screening may present an effective solution, this has not been rigorously assessed in a systematic review. A systematic review was performed using Ovid MEDLINE, PubMed, The Cochrane Library, Embase, Web of Science Core Collection, and Clinicaltrials.gov. All studies reporting the diagnostic accuracy of home-based screening tools for amblyopia among children were included. Studies involving orthoptist or ophthalmologist-led screening and adult subjects were excluded. The main outcome measure was the diagnostic accuracy expressed as sensitivity and specificity. Among 3670 studies identified, 28 were eligible for inclusion in our systematic review. The age range of patients were less than 1 month to 16 years old. 7 studies used internet-based tools, 16 used smartphone/tablet applications, 3 used digital cameras, and 3 used home-based questionnaires and visual acuity tools. All studies included a reference standard except one, which was a longitudinal study. 21 studies had full ophthalmological examination whilst 6 studies had validated visual acuity measurement tools as gold standards. Of the 27 studies which compared against a reference test, only 25 studies reported sensitivity and specificity values. Using the QUADAS-2 tool, 50% of studies were deemed to have applicability concern due to patient selection from tertiary centres and unclear methods for recruitment. There is a need to improve the quality of diagnostic accuracy studies, standardise thresholds for detecting amblyopia, and ensure consistent reporting of results. Further research is needed to evaluate the suitability of these tools for amblyopia screening., (© 2023. The Author(s).)

Normal high-density lipoprotein (nHDL) can induce angiogenesis in healthy individuals. However, HDL from patients with coronary artery disease undergoes various modifications, becomes dysfunctional (dHDL), and loses its ability to promote angiogenesis. Here, we identified a long non-coding RNA, HDRACA, that is involved in the regulation of angiogenesis by HDL. In this study, we showed that nHDL downregulates the expression of HDRACA in endothelial cells by activating WW domain-containing E3 ubiquitin protein ligase 2, which catalyzes the ubiquitination and subsequent degradation of its transcription factor, Kruppel-like factor 5, via sphingosine 1-phosphate (S1P) receptor 1. In contrast, dHDL with lower levels of S1P than nHDL were much less effective in decreasing the expression of HDRACA. HDRACA was able to bind to Ras-interacting protein 1 (RAIN) to hinder the interaction between RAIN and vigilin, which led to an increase in the binding between the vigilin protein and proliferating cell nuclear antigen (PCNA) mRNA, resulting in a decrease in the expression of PCNA and inhibition of angiogenesis. The expression of human HDRACA in a hindlimb ischemia mouse model inhibited the recovery of angiogenesis. Taken together, these findings suggest that HDRACA is involved in the HDL regulation of angiogenesis, which nHDL inhibits the expression of HDRACA to induce angiogenesis, and that dHDL is much less effective in inhibiting HDRACA expression, which provides an explanation for the decreased ability of dHDL to stimulate angiogenesis., (© 2023. West China Hospital, Sichuan University.)

Background/objectives: Handheld fundus cameras are portable and cheaper alternatives to table-top counterparts. To date there have been no studies comparing feasibility and clinical utility of handheld fundus cameras to table-top devices. We compare the feasibility and clinical utility of four handheld fundus cameras/retinal imaging devices (Remidio NMFOP, Volk Pictor Plus, Volk iNview, oDocs visoScope) to a table-top camera (Zeiss Visucam NM/FA )., Subjects/methods: Healthy participants (n = 10, mean age ± SD = 21.0 ± 0.9 years) underwent fundus photography with five devices to assess success/failure rates of image acquisition. Participants with optic disc abnormalities (n = 8, mean age ± SD = 26.8 ± 15.9) and macular abnormalities (n = 10, mean age ± SD = 71.6 ± 15.4) underwent imaging with the top three scoring fundus cameras. Images were randomised and subsequently validated by ophthalmologists masked to the diagnoses and devices used., Results: Image acquisition success rates (100%) were achieved in non-mydriatic and mydriatic settings for Zeiss, Remidio and Pictor, compared with lower success rates for iNview and oDocs. Image quality and gradeability were significantly higher for Zeiss, Remidio and Pictor (p < 0.0001) compared to iNview and oDocs. For cup:disc ratio estimates, similar levels of bias were seen for Zeiss (-0.09 ± SD:0.15), Remidio (-0.07 ± SD:0.14) and Pictor (-0.05 ± SD:0.16). Diagnostic sensitivities were highest for Zeiss (84.9%; 95% CI, 78.2-91.5%) followed by Pictor (78.1%; 95% CI, 66.6-89.5%) and Remidio (77.5%; 95% CI, 65.9-89.0%)., Conclusions: Remidio and Pictor achieve comparable results to the Zeiss table-top camera. Both devices achieved similar scores in feasibility, image quality, image gradeability and diagnostic sensitivity. This suggests that these devices potentially offer a more cost-effective alternative in certain clinical scenarios., (© 2022. The Author(s).)

Background/objectives: To characterise the patterns of presentation and diagnostic frequencies in Hospital Emergency Eye Care Services (HEECS) across 13 hospitals in England., Methods: Retrospective, cross-sectional, observational multi-centre (n = 13) study to assess HEECS attendances over a 28-day study period. Data derived included: number of consecutive attendances, patient demographics and diagnoses. Age and gender variations, the impact of day of the week on attendance patterns, diagnostic frequencies and estimates of the annual incidence and attendance rates were evaluated., Results: A total of 17,667 patient (mean ± standard deviation age = 49.6 ± 21.8 years) attendances were identified with an estimated HEECS annual new attendance rate of 31.0 per 1,000 population. Significantly more females (53%) than males (47%) attended HEECS (p < 0.001). Female attendances were 13% higher in those ≥50 years of age. Weekends were associated with a significant reduction in attendances compared to weekdays (χ 2  = 6.94, p < 0.001). Among weekdays, Mondays and Fridays were associated with significantly higher attendances compared with midweek (χ 2  = 2.20, p = 0.032). Presenting pathologies involving the external eye, cornea and conjunctiva accounted for 28.6% of the caseload., Conclusion: This is the largest multicentre study assessing attendance patterns in HEECS in England. We have, for the first time, observed a "weekend effect" in relation to attendance to HEECS. Differences in health-seeking behaviour and lack of awareness of HEECS weekend services may be partly attributed to the differences observed. Our findings, along with the type of presentations, have the potential to guide commissioners with future planning of HEECS., (© 2021. Crown.)

The history of the British Isles and Ireland is characterized by multiple periods of major cultural change, including the influential transformation after the end of Roman rule, which precipitated shifts in language, settlement patterns and material culture 1 . The extent to which migration from continental Europe mediated these transitions is a matter of long-standing debate 2-4 . Here we study genome-wide ancient DNA from 460 medieval northwestern Europeans-including 278 individuals from England-alongside archaeological data, to infer contemporary population dynamics. We identify a substantial increase of continental northern European ancestry in early medieval England, which is closely related to the early medieval and present-day inhabitants of Germany and Denmark, implying large-scale substantial migration across the North Sea into Britain during the Early Middle Ages. As a result, the individuals who we analysed from eastern England derived up to 76% of their ancestry from the continental North Sea zone, albeit with substantial regional variation and heterogeneity within sites. We show that women with immigrant ancestry were more often furnished with grave goods than women with local ancestry, whereas men with weapons were as likely not to be of immigrant ancestry. A comparison with present-day Britain indicates that subsequent demographic events reduced the fraction of continental northern European ancestry while introducing further ancestry components into the English gene pool, including substantial southwestern European ancestry most closely related to that seen in Iron Age France 5,6 ., (© 2022. The Author(s).)

In European and many African, Middle Eastern and southern Asian populations, lactase persistence (LP) is the most strongly selected monogenic trait to have evolved over the past 10,000 years 1 . Although the selection of LP and the consumption of prehistoric milk must be linked, considerable uncertainty remains concerning their spatiotemporal configuration and specific interactions 2,3 . Here we provide detailed distributions of milk exploitation across Europe over the past 9,000 years using around 7,000 pottery fat residues from more than 550 archaeological sites. European milk use was widespread from the Neolithic period onwards but varied spatially and temporally in intensity. Notably, LP selection varying with levels of prehistoric milk exploitation is no better at explaining LP allele frequency trajectories than uniform selection since the Neolithic period. In the UK Biobank 4,5 cohort of 500,000 contemporary Europeans, LP genotype was only weakly associated with milk consumption and did not show consistent associations with improved fitness or health indicators. This suggests that other reasons for the beneficial effects of LP should be considered for its rapid frequency increase. We propose that lactase non-persistent individuals consumed milk when it became available but, under conditions of famine and/or increased pathogen exposure, this was disadvantageous, driving LP selection in prehistoric Europe. Comparison of model likelihoods indicates that population fluctuations, settlement density and wild animal exploitation-proxies for these drivers-provide better explanations of LP selection than the extent of milk exploitation. These findings offer new perspectives on prehistoric milk exploitation and LP evolution., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Present-day people from England and Wales have more ancestry derived from early European farmers (EEF) than did people of the Early Bronze Age 1 . To understand this, here we generated genome-wide data from 793 individuals, increasing data from the Middle to the Late Bronze Age and Iron Age in Britain by 12-fold, and western and central Europe by 3.5-fold. Between 1000 and 875 BC, EEF ancestry increased in southern Britain (England and Wales) but not northern Britain (Scotland) due to incorporation of migrants who arrived at this time and over previous centuries, and who were genetically most similar to ancient individuals from France. These migrants contributed about half the ancestry of people of England and Wales from the Iron Age, thereby creating a plausible vector for the spread of early Celtic languages into Britain. These patterns are part of a broader trend of EEF ancestry becoming more similar across central and western Europe in the Middle to the Late Bronze Age, coincident with archaeological evidence of intensified cultural exchange 2-6 . There was comparatively less gene flow from continental Europe during the Iron Age, and the independent genetic trajectory in Britain is also reflected in the rise of the allele conferring lactase persistence to approximately 50% by this time compared to approximately 7% in central Europe where it rose rapidly in frequency only a millennium later. This suggests that dairy products were used in qualitatively different ways in Britain and in central Europe over this period., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Infantile nystagmus (IN) may result from aetiologies including albinism and FRMD7 mutations. IN has low prevalence, and twins with IN are rare. Whilst discordant presentation has been previously reported for IN, we present for the first time the comprehensive assessment of diagnostically discordant monozygotic twins. From a cohort of over 2000 patients, we identified twins and triplets discordant for nystagmus. Using next-generation sequencing, high-resolution infra-red pupil tracking and optical coherence tomography, we characterised differences in genotype and phenotype. Monozygotic twins (n = 1), dizygotic twins (n = 3) and triplets (n = 1) were included. The monozygotic twins had concordant TYR variants. No causative variants were identified in the triplets. Dizygotic twins had discordant variants in TYR, OCA2 and FRMD7. One unaffected co-twin demonstrated sub-clinical nystagmus. Foveal hypoplasia (FH) was noted in four of five probands. Both co-twins of the monozygotic pair and triplets displayed FH. In three families, at least one parent had FH without nystagmus. FH alone may be insufficient to develop nystagmus. Whilst arrested optokinetic reflex pathway development is implicated in IN, discordant twins raise questions regarding where differences in development have arisen. In unaffected monozygotes therefore, genetic variants may predispose to oculomotor instability, with variable expressivity possibly responsible for the discordance observed.

Our knowledge of ancient human population structure in sub-Saharan Africa, particularly prior to the advent of food production, remains limited. Here we report genome-wide DNA data from four children-two of whom were buried approximately 8,000 years ago and two 3,000 years ago-from Shum Laka (Cameroon), one of the earliest known archaeological sites within the probable homeland of the Bantu language group 1-11 . One individual carried the deeply divergent Y chromosome haplogroup A00, which today is found almost exclusively in the same region 12,13 . However, the genome-wide ancestry profiles of all four individuals are most similar to those of present-day hunter-gatherers from western Central Africa, which implies that populations in western Cameroon today-as well as speakers of Bantu languages from across the continent-are not descended substantially from the population represented by these four people. We infer an Africa-wide phylogeny that features widespread admixture and three prominent radiations, including one that gave rise to at least four major lineages deep in the history of modern humans.

Forager mobility tends to be high, although ethnographic studies indicate ecological factors such as resource abundance and reliability, population density and effective temperature influence the cost-to-benefit assessment of movement decisions. We investigate the evolution of mobility using an agent-based and spatially explicit cultural evolutionary model that considers the feedback between foragers and their environment. We introduce Outcomes Clustering, an approach to categorizing simulated system states arising from complex stochastic processes shaped by multiple interacting parameters. We find that decreased mobility evolves under conditions of high resource replenishment and low resource depletion, with a concomitant trend of increased population density and, counter-intuitively, decreased food incomes. Conversely, increased mobility co-occurs with lower population densities and higher food incomes. We replicate the well-known relationships between mobility, population density, and resource quality, while predicting reduced food income, and consequently the reduction in health status observed in early sedentary populations without the need to invoke factors such as reduced diet quality or increased pathogen loads.

This corrects the article DOI: 10.1038/nature25738.

From around 2750 to 2500 bc, Bell Beaker pottery became widespread across western and central Europe, before it disappeared between 2200 and 1800 bc. The forces that propelled its expansion are a matter of long-standing debate, and there is support for both cultural diffusion and migration having a role in this process. Here we present genome-wide data from 400 Neolithic, Copper Age and Bronze Age Europeans, including 226 individuals associated with Beaker-complex artefacts. We detected limited genetic affinity between Beaker-complex-associated individuals from Iberia and central Europe, and thus exclude migration as an important mechanism of spread between these two regions. However, migration had a key role in the further dissemination of the Beaker complex. We document this phenomenon most clearly in Britain, where the spread of the Beaker complex introduced high levels of steppe-related ancestry and was associated with the replacement of approximately 90% of Britain's gene pool within a few hundred years, continuing the east-to-west expansion that had brought steppe-related ancestry into central and northern Europe over the previous centuries.

Infantile nystagmus (IN) is a genetically heterogeneous disorder arising from variants of genes expressed within the developing retina and brain. IN presents a diagnostic challenge and patients often undergo numerous investigations. We aimed to develop and assess the utility of a next-generation sequencing (NGS) panel to enhance the diagnosis of IN. We identified 336 genes associated with IN from the literature and OMIM. NimbleGen Human custom array was used to enrich the target genes and sequencing was performed using HiSeq2000. Using reference genome material (NA12878), we show the sensitivity (98.5%) and specificity (99.9%) of the panel. Fifteen patients with familial IN were sequenced using the panel. Two authors were masked to the clinical diagnosis. We identified variants in 12/15 patients in the following genes: FRMD7 (n=3), CACNA1F (n=2), TYR (n=5), CRYBA1 (n=1) and TYRP1 (n=1). In 9/12 patients, the clinical diagnosis was consistent with the genetic diagnosis. In 3/12 patients, the results from the genetic diagnoses (TYR, CRYBA1 and TYRP1 variants) enabled revision of clinical diagnoses. In 3/15 patients, we were unable to determine a genetic diagnosis. In one patient, copy number variation analysis revealed a FRMD7 deletion. This is the first study establishing the clinical utility of a diagnostic NGS panel for IN. We show that the panel has high sensitivity and specificity. The genetic information from the panel will lead to personalised diagnosis and management of IN and enable accurate genetic counselling. This will allow development of a new clinical care pathway for IN.

Recent ancient DNA studies on European Neolithic human populations have provided persuasive evidence of a major migration of farmers originating from the Aegean, accompanied by sporadic hunter-gatherer admixture into early Neolithic populations, but increasing toward the Late Neolithic. In this context, ancient mitochondrial DNA data collected from the Neolithic necropolis of Gurgy (Paris Basin, France), the largest mitochondrial DNA sample obtained from a single archeological site for the Early/Middle Neolithic period, indicate little differentiation from farmers associated to both the Danubian and Mediterranean Neolithic migration routes, as well as from Western European hunter-gatherers. To test whether this pattern of differentiation could arise in a single unstructured population by genetic drift alone, we used serial coalescent simulations. We explore female effective population size parameter combinations at the time of the colonization of Europe 45000 years ago and the most recent of the Neolithic samples analyzed in this study 5900 years ago, and identify conditions under which population panmixia between hunter-gatherers/Early-Middle Neolithic farmers and Gurgy cannot be rejected. In relation to other studies on the current debate of the origins of Europeans, these results suggest increasing hunter-gatherer admixture into farmers' group migrating farther west in Europe.

The population history of Aboriginal Australians remains largely uncharacterized. Here we generate high-coverage genomes for 83 Aboriginal Australians (speakers of Pama-Nyungan languages) and 25 Papuans from the New Guinea Highlands. We find that Papuan and Aboriginal Australian ancestors diversified 25-40 thousand years ago (kya), suggesting pre-Holocene population structure in the ancient continent of Sahul (Australia, New Guinea and Tasmania). However, all of the studied Aboriginal Australians descend from a single founding population that differentiated ~10-32 kya. We infer a population expansion in northeast Australia during the Holocene epoch (past 10,000 years) associated with limited gene flow from this region to the rest of Australia, consistent with the spread of the Pama-Nyungan languages. We estimate that Aboriginal Australians and Papuans diverged from Eurasians 51-72 kya, following a single out-of-Africa dispersal, and subsequently admixed with archaic populations. Finally, we report evidence of selection in Aboriginal Australians potentially associated with living in the desert.

High-coverage whole-genome sequence studies have so far focused on a limited number of geographically restricted populations, or been targeted at specific diseases, such as cancer. Nevertheless, the availability of high-resolution genomic data has led to the development of new methodologies for inferring population history and refuelled the debate on the mutation rate in humans. Here we present the Estonian Biocentre Human Genome Diversity Panel (EGDP), a dataset of 483 high-coverage human genomes from 148 populations worldwide, including 379 new genomes from 125 populations, which we group into diversity and selection sets. We analyse this dataset to refine estimates of continent-wide patterns of heterozygosity, long- and short-distance gene flow, archaic admixture, and changes in effective population size through time as well as for signals of positive or balancing selection. We find a genetic signature in present-day Papuans that suggests that at least 2% of their genome originates from an early and largely extinct expansion of anatomically modern humans (AMHs) out of Africa. Together with evidence from the western Asian fossil record, and admixture between AMHs and Neanderthals predating the main Eurasian expansion, our results contribute to the mounting evidence for the presence of AMHs out of Africa earlier than 75,000 years ago., Competing Interests: The authors declare no competing financial interests.

Greek colonisation of South Italy and Sicily (Magna Graecia) was a defining event in European cultural history, although the demographic processes and genetic impacts involved have not been systematically investigated. Here, we combine high-resolution surveys of the variability at the uni-parentally inherited Y chromosome and mitochondrial DNA in selected samples of putative source and recipient populations with forward-in-time simulations of alternative demographic models to detect signatures of that impact. Using a subset of haplotypes chosen to represent historical sources, we recover a clear signature of Greek ancestry in East Sicily compatible with the settlement from Euboea during the Archaic Period (eighth to fifth century BCE). We inferred moderate sex-bias in the numbers of individuals involved in the colonisation: a few thousand breeding men and a few hundred breeding women were the estimated number of migrants. Last, we demonstrate that studies aimed at quantifying Hellenic genetic flow by the proportion of specific lineages surviving in present-day populations may be misleading.

We sequenced the genomes of a ∼7,000-year-old farmer from Germany and eight ∼8,000-year-old hunter-gatherers from Luxembourg and Sweden. We analysed these and other ancient genomes with 2,345 contemporary humans to show that most present-day Europeans derive from at least three highly differentiated populations: west European hunter-gatherers, who contributed ancestry to all Europeans but not to Near Easterners; ancient north Eurasians related to Upper Palaeolithic Siberians, who contributed to both Europeans and Near Easterners; and early European farmers, who were mainly of Near Eastern origin but also harboured west European hunter-gatherer related ancestry. We model these populations' deep relationships and show that early European farmers had ∼44% ancestry from a 'basal Eurasian' population that split before the diversification of other non-African lineages.

Autosomal-dominant idiopathic infantile nystagmus has been linked to 6p12 (OMIM 164100), 7p11.2 (OMIM 608345) and 13q31-q33 (OMIM 193003). PAX6 (11p13, OMIM 607108) mutations can also cause autosomal-dominant nystagmus, typically in association with aniridia or iris hypoplasia. We studied a large multigenerational white British family with autosomal-dominant nystagmus, normal irides and presenile cataracts. An SNP-based genome-wide analysis revealed a linkage to a 13.4-MB region on chromosome 11p13 with a maximum lod score of 2.93. A mutation analysis of the entire coding region and splice junctions of the PAX6 gene revealed a novel heterozygous missense mutation (c.227C>G) that segregated with the phenotype and is predicted to result in the amino-acid substitution of proline by arginine at codon 76 p.(P76R). The amino-acid variation p.(P76R) within the paired box domain is likely to destabilise the protein due to steric hindrance as a result of the introduction of a polar and larger amino acid. Eye movement recordings showed a significant intrafamilial variability of horizontal, vertical and torsional nystagmus. High-resolution in vivo imaging of the retina using optical coherence tomography (OCT) revealed features of foveal hypoplasia, including rudimentary foveal pit, incursion of inner retinal layers, short photoreceptor outer segments and optic nerve hypoplasia. Thus, this study presents a family that segregates a PAX6 mutation with nystagmus and foveal hypoplasia in the absence of iris abnormalities. Moreover, it is the first study showing detailed characteristics using eye movement recordings of autosomal-dominant nystagmus in a multigenerational family with a novel PAX6 mutation.

Variation within the gene for the proinflammatory cytokine interleukin (IL)-18 has been associated with inter-individual differences in levels of free protein and disease risk. We investigated the frequency of function-associated IL18 gene haplotypes in an extensive sample (n=2357) of African populations from across the continent. A previously identified five tagging SNP (single-nucleotide polymorphism) haplotype (here designated hGTATA), known to be associated with lower levels of IL-18, was observed at a frequency of 27% in a British population of recent European ancestry, but was found at low frequency (<8%) or completely absent in African populations. Potentially protective variants may, as a consequence, be found at low frequency in African individuals and may confer a difference in disease risk.

The Alps are one of the most significant geographical barriers in Europe and several isolated Swiss and Italian valleys retain the distinctive Ladin and Romansch languages, alongside the modern majority of Italian and German languages. Linguistically, Ladin belongs to the Romance languages, but some studies on mitochondrial DNA (mtDNA) variation have suggested a major Middle Eastern component to their genealogical origin. Furthermore, an observed high degree of within-population diversity has been interpreted as reflecting long-standing differentiation from other European populations and the absence of a major bottleneck in Ladin population history. To explore these issues further, we examined Y chromosome and mtDNA variation in two samples of Ladin speakers, two samples of German speakers and one sample of metropolitan Italian speakers. Our results (1) indicate reduced diversity in the Ladin-speaking and isolated German-speaking populations when compared to a sample of metropolitan Italian speakers, (2) fail to identify haplotypes that are rare in other European populations that other researchers have identified, and (3) indicate different Middle Eastern components to Ladin ancestry in different localities. These new results, in combination with Bayesian estimation of demographic parameters of interest (population size, population growth rate, and Palaeolithic/Neolithic admixture proportions) and phylogeographic analysis, suggest that the Ladin groups under study are small genetically isolated populations (subject to strong genetic drift), having a predominantly European ancestry, and in one locality, may have a greater Palaeolithic component to that ancestry than their neighbours.

The giant deer, or 'Irish elk', has featured extensively in debates on adaptation, sexual selection, and extinction. Its huge antlers--the largest of any deer species, living or extinct--formed a focus of much past work. Yet the phylogenetic position of the giant deer has remained an enigma. On the basis of its flattened antlers, the species was previously regarded as closely related to the living fallow deer. Recent morphological studies, however, have challenged that view and placed the giant deer closer to the living red deer or wapiti. Here we present a new phylogenetic analysis encompassing morphological and DNA sequence evidence, and find that both sets of data independently support a sister-group relationship of giant and fallow deer. Our results include the successful extraction and sequencing of DNA from this extinct species, and highlight the value of a joint molecular and morphological approach.