DNA sequence information underpins genetic research, enabling discoveries of important biological or medical benefit. Sequencing projects have traditionally employed long (400–800 bp) reads, but the existence of reference sequences for the human and many other genomes makes it possible to develop new, fast approaches to re-sequencing, whereby shorter reads are compared to a reference to identify intra-species genetic variation. We report an approach that generates several billion bases of accurate nucleotide sequence per experiment at low cost. Single molecules of DNA are attached to a flat surface, amplified in situ and used as templates for synthetic sequencing with fluorescent reversible terminator deoxyribonucleotides. Images of the surface are analysed to generate high quality sequence. We demonstrate application of this approach to human genome sequencing on flow-sorted X chromosomes and then scale the approach to determine the genome sequence of a male Yoruba from Ibadan, Nigeria. We build an accurate consensus sequence from >30x average depth of paired 35-base reads. We characterise four million SNPs and four hundred thousand structural variants, many of which are previously unknown. Our approach is effective for accurate, rapid and economical whole genome re-sequencing and many other biomedical applications.

We report on our search for microlensing towards the Large Magellanic Cloud (LMC). Analysis of 5.7 years of photometry on 11.9 million stars in the LMC reveals 13 -17 microlensing events. A detailed treatment of our detection efficiency shows that this is significantly more than the ∼ 2 to 4 events expected from lensing by known stellar populations. The timescales ( t ) of the events range from 34 to 230 days. We estimate the microlensing optical depth towards the LMC from events with 2 < t < 400 days to be τ 400 2 = 1.2 +0.4 −0.3 × 10 −7 , with an additional 20% to 30% of systematic error. The spatial distribution of events is mildly inconsistent with LMC/LMC disk self-lensing, but is consistent with an extended lens distribution such as a Milky Way or LMC halo. Interpreted in the context of a Galactic dark matter halo, consisting partially of compact objects, a maximum likelihood analysis gives a MACHO halo fraction of 20% for a typical halo model with a 95% confidence interval of 8% to 50%. A 100% MACHO halo is ruled out at the 95% C.L. for all except our most extreme halo model. Interpreted as a Galactic halo population, the most likely MACHO mass is between 0.15 M ⊙ and 0.9 M ⊙ , depending on the halo model, and the total mass in MACHOs out to 50 kpc is found to be 9 +4 −3 × 10 10 M ⊙ , independent of the halo model. These results are marginally consistent with our previous results, but are lower by about a factor of two. This is mostly due to Poisson noise because with 3.4 times more exposure and increased sensitivity to long timescale events, we did not find the expected factor of ∼ 4 more events. Besides a larger data set, this work also includes an improved efficiency determination, improved likelihood analysis, and more thorough testing of systematic errors, especially with respect to the treatment of potential backgrounds to microlensing. We note that an important source of background are supernovae in galaxies behind the LMC.

The MACHO Project is a search for dark matter in the form of massive compact halo objects (MACHOs). Photometric monitoring of millions of stars in the Large Magellanic Cloud (LMC), Small Magellanic Cloud (SMC), and Galactic bulge is used to search for gravitational microlensing events caused by these otherwise invisible objects. Analysis of the Ðrst 2.1 yr of photometry of 8.5 million stars in the LMC reveals eight candidate microlensing events. This is substantially more than the number expected (D1.1) from lensing by known stellar populations. The timescales (t) of the events range from 34 to 145 days. We estimate the total microlensing optical depth toward the LMC from events with days to be based upon our eight event sample. This exceeds the 2 \ tü \ 200 q 2 200 \ 2.9~0 .9 1.4 ] 10~7 optical depth, expected from known stars, and the di †erence is to be compared q backgnd \ 0.5 ] 10~7, with the optical depth predicted for a "" standard ÏÏ halo composed entirely of MACHOs : q halo \ 4.7 To compare with Galactic halo models, we perform likelihood analyses on the full eight-event ] 10~7. sample and a six-event subsample (which allows for two events to be caused by a nonhalo "" background ÏÏ). This gives a fairly model-independent estimate of the halo mass in MACHOs within 50 kpc of which is about half of the "" standard halo ÏÏ value. We also Ðnd a most prob-2.0~0 .71.2 ] 1011 M _ , able MACHO mass of although this value is strongly model dependent. In addition, the 0.5~0 .2 0.3 M _ , absence of short duration events places stringent upper limits on the contribution of low-mass MACHOs : objects from 10~4 to 0.03 contribute of the "" standard ÏÏ dark halo.