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After the main out-of-Africa event, humans interbred with Neanderthals leaving 1-2% of Neanderthal DNA scattered in small fragments in all non-African genomes today1,2. Here we investigate the size distribution of these fragments in non-African genomes3. We find consistent differences in fragment length distributions across Eurasia with 11% longer fragments in East Asians than in West Eurasians. By comparing extant populations and ancient samples, we show that these differences are due to a different rate of decay in length by recombination since the Neanderthal admixture. In line with this, we observe a strong correlation between the average fragment length and the accumulation of derived mutations, similar to what is expected by changing the ages at reproduction as estimated from trio studies4. Altogether, our results suggest consistent differences in the generation interval across Eurasia, by up to 20% (e.g. 25 versus 30 years), over the past 40,000 years. We use sex-specific accumulations of derived alleles to infer how these changes in generation intervals between geographical regions could have been mainly driven by shifts in either male or female age of reproduction, or both. We also find that previously reported variation in the mutational spectrum5 may be largely explained by changes to the generation interval and not by changes to the underlying mutational mechanism. We conclude that Neanderthal fragment lengths provide unique insight into differences of a key demographic parameter among human populations over the recent history.

Genes in the major histocompatibility complex (MHC, also known as HLA) play a critical role in the immune response and variation within the extended 4-Mb region shows association with major risks of many diseases. Yet, deciphering the underlying causes of these associations is difficult because the MHC is the most polymorphic region of the genome with a complex linkage disequilibrium structure. Here, we reconstruct full MHC haplotypes from de novo assembled trios without relying on a reference genome and perform evolutionary analyses. We report 100 full MHC haplotypes and call a large set of structural variants in the regions for future use in imputation with GWAS data. We also present the first complete analysis of the recombination landscape in the entire region and show how balancing selection at classical genes have linked effects on the frequency of variants throughout the region.

BACKGROUND: The adaptive immune response intrinsically depends on hypervariable human leukocyte antigen (HLA) genes. Concomitantly, correct HLA phenotyping is crucial for successful donor-patient matching in organ transplantation. The cost and technical limitations of current laboratory techniques, together with advances in next-generation sequencing (NGS) methodologies, have increased the need for precise computational typing methods.RESULTS: We tested two widespread HLA typing methods using high quality full genome sequencing data from 150 individuals in 50 family trios from the Genome Denmark project. First, we computed descendant accuracies assessing the agreement in the inheritance of alleles from parents to offspring. Second, we compared the locus-specific homozygosity rates as well as the allele frequencies; and we compared those to the observed values in related populations. We provide guidelines for testing the accuracy of HLA typing methods by comparing family information, which is independent of the availability of curated alleles.CONCLUSIONS: Although current computational methods for HLA typing generally provide satisfactory results, our benchmark - using data with ultra-high sequencing depth - demonstrates the incompleteness of current reference databases, and highlights the importance of providing genomic databases addressing current sequencing standards, a problem yet to be resolved before benefiting fully from personalised medicine approaches HLA phenotyping is essential.

The human Y-chromosome does not recombine across its male-specific part and is therefore an excellent marker of human migrations. It also plays an important role in male fertility. However, its evolution is difficult to fully understand because of repetitive sequences, inverted repeats and the potentially large role of gene conversion. Here we perform an evolutionary analysis of 62 Y-chromosomes of Danish descent sequenced using a wide range of library insert sizes and high coverage, thus allowing large regions of these chromosomes to be well assembled. These include 17 father-son pairs, which we use to validate variation calling. Using a recent method that can integrate variants based on both mapping and de novo assembly, we genotype 10898 SNVs and 2903 indels (max length of 27241 bp) in our sample and show by father-son concordance and experimental validation that the non-recurrent SNP and indel variation on the Y chromosome tree is called very accurately. This includes variation called in a 0.9 Mb centromeric heterochromatic region, which is by far the most variable in the Y chromosome. Among the variation is also longer sequence-stretches not present in the reference genome but shared with the chimpanzee Y chromosome. We analyzed 2.7 Mb of large inverted repeats (palindromes) for variation patterns among the two palindrome arms and identified 603 mutation and 416 gene conversions events. We find clear evidence for GC-biased gene conversion in the palindromes (and a balancing AT mutation bias), but irrespective of this, also a strong bias towards gene conversion towards the ancestral state, suggesting that palindromic gene conversion may alleviate Muller’s ratchet. Finally, we also find a large number of large-scale gene duplications and deletions in the palindromic regions (at least 24) and find that such events can consist of complex combinations of simultaneous insertions and deletions of long stretches of the Y chromosome., Author summary The Y chromosome is extraordinary in many respects; it is non-recombining along most of its length, it carries many testis-expressed genes that are often found in palindromes and thus in several copies, and it is generally highly repetitive with very few unique genes. Its evolutionary process is not well understood in general because short-read mapping in such complex sequence is difficult. We combine de novo assembly and mapping to investigate evolution in more than 60% of the length of 62 Y chromosomes of Danish descent. We find that Y chromosome evolution is very dynamic even among the set of closely related Y chromosomes in Denmark with many cases of complex duplications and deletions of large regions including whole genes, clear evidence of GC-biased gene conversion in the palindromes and a tendency for gene conversion to revert mutations to their ancestral state.

Vores viden vedrørende moderne og arkaiske mennesker er blevet forbedret utrolig meget over de sidste årti. Men der er stadig mange ubesvarede spørgsmål.Traditionelle metoder til at undersøge strukturel variation i komplekse regioner såsom Y kromosomet eller ved at benytte gammelt DNA er ved at nå deres grænser. Derfor er det nødvendigt at udvikle nye metoder.Vi viser at ved at bruge en kombination af traditionelle Next generation sequencing metoder, de novo assemblies og k-mer baseret variant genotyping at vi er i stand til at detektere variation på y kromosomet der tidligere ikke kunne findes, endda i komplekse regioner.Vi viser at denne k-mer baseret måde at genotype på, er i stand til at finde omkring 200.000 strukturelle varianter i Neandertalere som også findes i moderne mennesker. 4.537 af disse varianter formodes at haveen effekt og i fremtiden vil de sandsynligvis kunne hjælpe med at finde ud af hvilken funktion de har i moderne og arkaiske mennesker.Til slut, har vi udviklet in metode til at detektere områder i genomet der kommer fra Neandertalere. Vi finder disse regioner uden at bruge reference Neandertal genomet eller reference Denisova genomet. Vi viser at vores nye metode er i stand til at finde en stor andel af de arkaiske segmenter.

Objective: The objective of this study was to investigate the attitudes towards choice architectural nudge interventions aiming to increase vegetable intake among Danish teenagers in a school context, and which factors influence these attitudes.Methodology: Cross-sectional data were collected through an online quantitative questionnaire, which was developed, validated and distributed to assess factors associated with attitude towards choice architectural nudge interventions. Data analysis included descriptive statistics, factor analysis and structural equation modelling. A total of 408 respondents (78% female) with a mean age of 18(±1.3) spread throughout Denmark provided sufficient responses.Results: The structural equation model revealed that healthy buffet ha- bits and opinions of where the responsibility of healthy eating lies had the strongest positive association with attitude towards choice architectural nudge interventions. Also, social norms were positively associated with the outcome. Perceived vegetable intake and buffet habits attaching importance to animal welfare and organic food had a negative association.The descriptive analysis found that the respondents were generally positive towards less intrusive nudges and displayed a more negative attitude towards those targeting their self-image. Further, the respondents considered it to be acceptable for the school to attempt to intervene with their health-related behaviour, but essentially they saw it as neither the school's obligation nor responsibility.Key findings: Healthy buffet habits and opinions of where the responsibility of healthy eating lies were found to have the strongest positive association with attitude towards choice architectural nudge interventions. In general, the respondents were predominantly positive towards the use of less intrusive choice architectural nudge interventions, while negative attitudes were expressed towards nudges targeting the respondents' self-image.

Objective: To test the effectiveness of three types of choice architectural nudges to promote vegetable consumption among Danish people. The experiment aims at providing evidence on the influence of automatic processing system in the food choice situation in an all you can eat buffet serving. Methodology: Experimental cross-over design study in the FoodScape Lab, comparing control to exposure of three nudges: Nudge 1: Natural green - priming vegetable-choosing behaviour. Nudge 2: Having a pre-weighed (200g) fixed salad as default to the main course, and Nudge 3: presenting each component of the salad separately to increase choices compared to a pre-mixed salad. Results: A total of 92 people (dropout rate=21 %) partook in the study (60.2% female) with an average age of 26.5. Nudge 1 (N=27) found a significant decrease in total energy consumption due to high decrease in meat consumption (p

Objective: This study assessed the combined effect of two choice archi- tectural nudges as a means to increase fruit and vegetable consumption among male university students.Methodology: This single one-day lunch meal study was conducted in a Food Scape Laboratory. A control group (n=32) and an intervention group (n=33) were recruited to attend an ad libitum self-serve buffet at two different timeslots. Two choice architectural nudges were applied in the intervention group; the fruit and vegetables were placed at the be- ginning of the buffet and separated in eight separate bowls to increase visual variety. The self-served amount (g) of food components was mea- sured using high intelligence equipment.Results: The amount (g) of self-served fruit and vegetables was significantly higher in the intervention group (p =.005). The total energy consumed (kJ) was significantly lower in the intervention group (p=.01), while there was no significant difference in the total amount (g) of self- served food between the two groups (p=.326).Key Findings: This study found convincing evidence for the combined effect of two choice architectural nudges as a means to increase the amount of self-served fruit and vegetables among male university students. 8ased on these findings it is suggested that choice architecture could be used as a supplement to already existing strategies in the pro- motion of public health nutrition.

Objective: The primary objective of this review was to update the current evidence-base for the use of choice architecture as a means to change eating behaviour in self-service eating settings, hence potentially reducing energy intake.Methodology: 12 databases were searched systematically for experimental studies with predefined choice architectural interventions in the period June 2011 - March 2012. The 12 included studies were grouped according to type of interventions and underwent a narrative synthesis. An update of the review was conducted during the summer of 2014. Results: The evidence indicates that (i) health labelling at point-of-purchase is associated with healthier food choice, whilst (ii) manipulating the plate and cutlery size has an inconclusive effect on consumption volume. Finally, (iii) assortment manipulation and (iv) payment option manipulation was associated with healthier food choices. The majority of studies were of very weak quality and future research should emphasize a real-life setting and compare their results with the effect of other more well-established interventions on food behaviour in self-service eating settings.Key findings: An increasing interest in the topic of choice architecture and nudging has increased the scientific output since the last review. There is a clear limitation in the lack of a clear definitions and theoretical foundation.