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However, as the number of sequences increases and especially in genome-wide studies that involve many MSAs it is impossible to manually curate all alignments. Furthermore, manual curation is subjective. And finally, even the best expert cannot confidently align the more ambiguous cases of highly diverged sequences. In such cases it is common practice to use automatic procedures to exclude unreliably aligned regions from the MSA. For the purpose of phylogeny reconstruction (see below) the Gblocks program is widely used to remove alignment blocks suspect of low quality, according to various cutoffs on the number of gapped sequences in alignment columns.<ref name="castresana2000">{{cite journal | vauthors = Castresana J | title = Selection of conserved blocks from multiple alignments for their use in phylogenetic analysis | journal = Mol. Biol. Evol. | volume = 17 | issue = 4 | pages = 540–52 | date = April 2000 | pmid = 10742046 | doi = 10.1093/oxfordjournals.molbev.a026334 | doi-access = free }}</ref> However, these criteria may excessively filter out regions with insertion/deletion events that may still be aligned reliably, and these regions might be desirable for other purposes such as detection of positive selection. A few alignment algorithms output site-specific scores that allow the selection of high-confidence regions. Such a service was first offered by the SOAP program,<ref name="loytynojaMilinkovitch2001">{{cite journal | vauthors = Löytynoja A, Milinkovitch MC | title = SOAP, cleaning multiple alignments from unstable blocks | journal = Bioinformatics | volume = 17 | issue = 6 | pages = 573–4 | date = June 2001 | pmid = 11395440 | doi = 10.1093/bioinformatics/17.6.573 | doi-access = free }}</ref> which tests the robustness of each column to perturbation in the parameters of the popular alignment program CLUSTALW. The T-Coffee program<ref name=poirotOTooleNotredame2003>{{cite journal | vauthors = Poirot O, O'Toole E, Notredame C | title = Tcoffee@igs: A web server for computing, evaluating and combining multiple sequence alignments | journal = Nucleic Acids Res. | volume = 31 | issue = 13 | pages = 3503–6 | date = July 2003 | pmid = 12824354 | pmc = 168929 | doi = 10.1093/nar/gkg522 }}</ref> uses a library of alignments in the construction of the final MSA, and its output MSA is colored according to confidence scores that reflect the agreement between different alignments in the library regarding each aligned residue. Its extension, [http://tcoffee.crg.cat/tcs TCS] : ('''T'''ransitive '''C'''onsistency '''S'''core), uses T-Coffee libraries of pairwise alignments to evaluate any third party MSA. Pairwise projections can be produced using fast or slow methods, thus allowing a trade-off between speed and accuracy.<ref name=TCS2014MBE>{{cite journal|last=Chang|first=JM|author2=Di Tommaso, P | author3 = Notredame, C|title=TCS: A New Multiple Sequence Alignment Reliability Measure to Estimate Alignment Accuracy and Improve Phylogenetic Tree Reconstruction.|journal=Molecular Biology and Evolution|date=Jun 2014|volume=31|issue=6|pages=1625–37|doi=10.1093/molbev/msu117|pmid=24694831|url=http://mbe.oxfordjournals.org/content/31/6/1625|doi-access=free}}</ref><ref name=TCS_2015_NAR>{{cite journal | vauthors = Chang JM, Di Tommaso P, Lefort V, Gascuel O, Notredame C | title = TCS: a web server for multiple sequence alignment evaluation and phylogenetic reconstruction | journal = Nucleic Acids Res. | volume = 43 | issue = W1 | pages = W3–6 | date = July 2015 | pmid = 25855806 | pmc = 4489230 | doi = 10.1093/nar/gkv310 }}</ref> Another alignment program that can output an MSA with confidence scores is FSA,<ref name=bradley2009>{{cite journal | vauthors = Bradley RK, Roberts A, Smoot M, Juvekar S, Do J, Dewey C, Holmes I, Pachter L | title = Fast statistical alignment | journal = PLoS Comput. Biol. | volume = 5 | issue = 5 | pages = e1000392 | date = May 2009 | pmid = 19478997 | pmc = 2684580 | doi = 10.1371/journal.pcbi.1000392 | bibcode = 2009PLSCB...5E0392B }}</ref> which uses a statistical model that allows calculation of the uncertainty in the alignment. The HoT (Heads-Or-Tails) score can be used as a measure of site-specific alignment uncertainty due to the existence of multiple co-optimal solutions.<ref name=landanGraur2008>{{cite book | vauthors = Landan G, Graur D | title = Local reliability measures from sets of co-optimal multiple sequence alignments | journal = Pac Symp Biocomput | volume = | issue = | pages = 15–24 | date = 2008 | pmid = 18229673 | doi = 10.1142/9789812776136_0003 |isbn = 978-981-277-608-2 }}</ref> The GUIDANCE program<ref name="penn2010">{{cite journal | vauthors = Penn O, Privman E, Landan G, Graur D, Pupko T | title = An alignment confidence score capturing robustness to guide tree uncertainty | journal = Mol. Biol. Evol. | volume = 27 | issue = 8 | pages = 1759–67 | date = August 2010 | pmid = 20207713 | pmc = 2908709 | doi = 10.1093/molbev/msq066 }}</ref> calculates a similar site-specific confidence measure based on the robustness of the alignment to uncertainty in the guide tree that is used in progressive alignment programs. An alternative, more statistically justified approach to assess alignment uncertainty is the use of probabilistic evolutionary models for joint estimation of phylogeny and alignment. A Bayesian approach allows calculation of posterior probabilities of estimated phylogeny and alignment, which is a measure of the confidence in these estimates. In this case, a posterior probability can be calculated for each site in the alignment. Such an approach was implemented in the program BAli-Phy.<ref name="redelingsSuchard2005">{{cite journal | vauthors = Redelings BD, Suchard MA | title = Joint Bayesian estimation of alignment and phylogeny | journal = Syst. Biol. | volume = 54 | issue = 3 | pages = 401–18 | date = June 2005 | pmid = 16012107 | doi = 10.1080/10635150590947041 | doi-access = free }}</ref>
There are free
==Phylogenetic use==
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