Alex Mentzer

A genomic history of Aboriginal Australia

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.

Distinguishing orofacial granulomatosis from crohn's disease: Two separate disease entities?

Background: Orofacial granulomatosis (OFG) is a rare chronic inflammatory disease of unknown etiology sharing histological features with Crohns disease (CD). This study aimed to 1) define the clinical presentation of OFG, 2) establish differentiating features for those with CD, 3) examine if onset of OFG is predictive of CD, and 4) establish differentiating features for children. Methods: Data were extracted from medical notes (n = 207) for demographics, clinical features, blood parameters, diagnosis of CD, and treatments for patients with OFG. Results: Ninety‐seven patients (47%) were female. The lips (184/203; 91%) and buccal mucosa (151/203; 74%) were mainly affected. Forty‐six (22%) had intestinal CD. Ulcers (24/46; 46% versus 29/159; 15%, P = <0.001) were more common in patients with CD as was a raised C‐reactive protein (24/33; 73% versus 60/122; 49%, P = 0.016) and abnormal full blood count (19/41; 46% versus 35/150; 23%). The buccal‐sulcus (12/44; 27% versus 20/158; 13%, P = 0.019) was more often affected in those with CD. Half the patients with CD were diagnosed prior to onset of OFG. The remainder were diagnosed after. The incidence of CD is similar for children (16/69; 23%) and adults (29/132; 22%), although oral onset in childhood is more likely to occur prior to diagnosis of CD. Conclusions: OFG mainly presents in young adults with lip and buccal involvement. Abnormalities in inflammatory markers, hematology and oral features of ulceration, and buccal‐sulcal involvement are factors more commonly associated with CD. Initial presentation of OFG does not necessarily predict development of CD, although this is more likely in childhood. (Inflamm Bowel Dis 2011;)

Optimizing the use of thiopurines in inflammatory bowel disease

Immunomodulator drugs, of which thiopurines can be considered the backbone, are widely used in the treatment of inflammatory bowel disease. They have been shown to be highly effective and safe; however, a significant proportion of patients are deemed to have a poor response or suffer adverse reactions. Knowing how to monitor and optimize thiopurine therapy in these scenarios is crucial to effective management. We discuss the metabolism of thiopurines, the use of enzyme/metabolite testing to guide treatment, as well as strategies to circumvent toxicity and side effects, such as allopurinol coprescription. The indications, use in pregnancy, safety profile and duration of thiopurine therapy are also discussed.

Searching for the human genetic factors standing in the way of universally effective vaccines

Vaccines have revolutionized modern public health. The effectiveness of some vaccines is limited by the variation in response observed between individuals and across populations. There is compelling evidence that a significant proportion of this variability can be attributed to human genetic variation, especially for those vaccines administered in early life. Identifying and understanding the determinants of this variation could have a far-reaching influence upon future methods of vaccine design and deployment. In this review, we summarize the genetic studies that have been undertaken attempting to identify the genetic determinants of response heterogeneity for the vaccines against hepatitis B, measles and rubella. We offer a critical appraisal of these studies and make a series of suggestions about how modern genetic techniques, including genome-wide association studies, could be used to characterize the genetic architecture of vaccine response heterogeneity. We conclude by suggesting how the findings from such studies could be translated to improve vaccine effectiveness and target vaccination in a more cost-effective manner.

Association between a common immunoglobulin heavy chain allele and rheumatic heart disease risk in Oceania

The indigenous populations of the South Pacific experience a high burden of rheumatic heart disease (RHD). Here we report a genome-wide association study (GWAS) of RHD susceptibility in 2,852 individuals recruited in eight Oceanian countries. Stratifying by ancestry, we analysed genotyped and imputed variants in Melanesians (607 cases and 1,229 controls) before follow-up of suggestive loci in three further ancestral groups: Polynesians, South Asians and Mixed or other populations (totalling 399 cases and 617 controls). We identify a novel susceptibility signal in the immunoglobulin heavy chain (IGH) locus centring on a haplotype of nonsynonymous variants in the IGHV4-61 gene segment corresponding to the IGHV4-61*02 allele. We show each copy of IGHV4-61*02 is associated with a 1.4-fold increase in the risk of RHD (odds ratio 1.43, 95% confidence intervals 1.27–1.61, P=4.1 × 10−9). These findings provide new insight into the role of germline variation in the IGH locus in disease susceptibility.

Is it all cerebral toxoplasmosis

A 43-year-old Nigerian man presented in April, 2010, with a 1 week history of progressive left leg weakness, urinary incontinence, and weight loss. Neurological examination showed left-sided neglect and hemiparesis. Physical examination was otherwise unremarkable. Blood test results were normal. MRI of the brain showed multiple bilateral ring-enhancing lesions; the largest was centred on the right basal ganglia with pronounced mass eff ect (fi gure A). Treatment for cerebral toxoplasmosis was initiated with sulfadiazine (15 mg/kg, four times daily), pyrimethamine (200 mg loading dose followed by 75 mg daily), and folinic acid (10 mg daily). IgG active against toxoplasma was detected and HIV-1 infection was confi rmed with a baseline viral load of 870 976 copies/mL and CD4 T-cell count of 68 cells/μL (11%). Left arm tone and power normalised after 24 h of treatment, but there was residual left leg weakness and over the next 2 weeks our patient developed a new rightsided hypertonia and he became progressively mute. Repeat MRI showed moderate improvement of the changes in the right hemisphere with reduction of vasogenic oedema (fi gure B). There was, however, a gradual progression of a solid mass in the left corona radiata on MRI; on fl uorine-18-labelled fl uorodeoxyglucose PET-CT (done 3 weeks after presentation) it showed signifi cantly higher uptake than the other lesions, which had lower uptake than normal cortex (see webappendix). These fi ndings suggested dual pathology, with lymphoma being the most likely secondary diagnosis. Despite initiation of highly active antiretroviral therapy and high-dose dexamethasone, our patient became less responsive and had generalised seizures necessitating ventilation 4 weeks after the initial presentation. A biopsy of the solid mass in the left hemisphere confi rmed primary cerebral diff use large B-cell lymphoma. We started our patient on high-dose methotrexate then cytarabine but there was no improvement. 8 weeks after initial presentation, treatment was withdrawn and the patient died on July 3, 2010. Cerebral toxoplasmosis is one of the commonest presenting diagnoses in advanced HIV disease. Primary cerebral lymphoma is uncommon, but over 30% of cases are associated with HIV infection. Diff erentiation of the two pathologies is diffi cult owing to the similar clinical and radiological presentation, but MRI and PET are the imaging modalities of choice, and tissue diagnosis is the gold standard. Prognosis in HIV-infected patients with primary cerebral lymphoma is poor, with median survival of 2 months, but antiretroviral therapy may improve life expectancy. The choice of chemotherapy tends to be a methotrexate-based regimen with a combination of other agents such as vincristine or cytarabine. This case serves as a reminder of the complexity of patients with late presentation of HIV infection in the UK, where the Health Protection Agency estimates that around 30% of individuals with HIV infection are undiagnosed and a similar percentage of those diagnosed present late. The HIV-infected population is predicted to reach 100 000 by 2012, therefore, the proportion of undiagnosed patients and late presenters must be reduced. Recent guidance from the Health Protection Agency recommends implementation of screening in health-care settings where the prevalence of HIV infection is higher than 2 per 1000, which may help to achieve this goal.

Backache with Fever: A Unique Presentation of Advanced HIV Infection

This case report follows a previously asymptomatic man who presented with common, non-specifi c symptoms and was diagnosed with a rare complication of non-typhi Salmonella infection. Further investigations revealed the presence of advanced HIV infection and with subsequent follow up a number of co-existing pathologies were diagnosed with fatal consequences. This case serves as an example of the complexity of patients diagnosed with late HIV disease. It serves as a clear reminder to all clinicians to have a low threshold for testing for HIV and highlights the need to introduce an opt-out system for HIV testing in all acute healthcare settings with a high prevalence of HIV infection.

Language continuity despite population replacement in Remote Oceania.

Recent genomic analyses show that the earliest peoples reaching Remote Oceania—associated with Austronesian-speaking Lapita culture—were almost completely East Asian, without detectable Papuan ancestry. However, Papuan-related genetic ancestry is found across present-day Pacific populations, indicating that peoples from Near Oceania have played a significant, but largely unknown, ancestral role. Here, new genome-wide data from 19 ancient South Pacific individuals provide direct evidence of a so-far undescribed Papuan expansion into Remote Oceania starting ~2,500 yr bp, far earlier than previously estimated and supporting a model from historical linguistics. New genome-wide data from 27 contemporary ni-Vanuatu demonstrate a subsequent and almost complete replacement of Lapita-Austronesian by Near Oceanian ancestry. Despite this massive demographic change, incoming Papuan languages did not replace Austronesian languages. Population replacement with language continuity is extremely rare—if not unprecedented—in human history. Our analyses show that rather than one large-scale event, the process was incremental and complex, with repeated migrations and sex-biased admixture with peoples from the Bismarck Archipelago.Genome-wide data from ancient and modern individuals in Remote Oceania indicate population replacement but language continuity over the past 2,500 years. Papuan migrations led to almost complete genetic replacement of in situ East Asian-derived populations, but not replacement of Austronesian languages.

Genetic Association Analysis Reveals Differences in the Contribution of NOD2 Variants to the Clinical Phenotypes of Orofacial Granulomatosis.

Background:Orofacial granulomatosis (OFG) is a rare, inflammatory disorder of the mouth, in which some patients also have intestinal Crohns disease (CD). The etiology remains largely unknown, although there is a high prevalence of atopy, and oral granulomas are also seen in other immune disorders particularly CD and sarcoidosis. We investigated whether genetic variants associated with an increased risk of CD, sarcoidosis, or atopy were also associated with susceptibility to OFG. Methods:Patients were stratified clinically as isolated oral manifestations (OFG only) or concurrent intestinal CD (OFG+CD). We genotyped 201 patients and 1023 healthy controls for risk variants in NOD2, IRGM, IL23R, ATG16L1 (CD), BTNL2 (sarcoidosis), and FLG (atopy). The coding regions of the NOD2 gene were screened for rare, potentially pathogenic variants in OFG. Results:A combined analysis of 3 CD-risk variants in NOD2 showed no association with any OFG subgroup. NOD2 p.L1007insC was associated with OFG+CD (P = 0.023) and IL23R p.R381Q with all OFG (P = 0.031). The sarcoidosis risk variant rs2076530 in BTNL2 was associated with all OFG (P = 0.013). We identified 7 rare missense NOD2 alleles in 8 individuals with OFG, 4 OFG-only patients and 4 patients with OFG+CD. There was a significant enrichment of NOD2 variants in the OFG+CD group compared to the OFG-only group (P = 0.008, common variants; P = 0.04, all common and rare variants). Conclusions:Our findings suggest that genetic variants in NOD2 are only associated with OFG in patients with concurrent intestinal disease. A genome-wide association scan is needed to fully define the genetic architecture of OFG.

Long reads: their purpose and place

Abstract In recent years long-read technologies have moved from being a niche and specialist field to a point of relative maturity likely to feature frequently in the genomic landscape. Analogous to next generation sequencing, the cost of sequencing using long-read technologies has materially dropped whilst the instrument throughput continues to increase. Together these changes present the prospect of sequencing large numbers of individuals with the aim of fully characterizing genomes at high resolution. In this article, we will endeavour to present an introduction to long-read technologies showing: what long reads are; how they are distinct from short reads; why long reads are useful and how they are being used. We will highlight the recent developments in this field, and the applications and potential of these technologies in medical research, and clinical diagnostics and therapeutics.